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Review

Current Perspectives on Functional Involvement of Micropeptides in Virus–Host Interactions

1
Key Laboratory of Animal Pathogen Infection and Immunology of Fujian Province, College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China
2
Key Laboratory of Fujian-Taiwan Animal Pathogen Biology, College of Animal Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2025, 26(8), 3651; https://doi.org/10.3390/ijms26083651
Submission received: 10 February 2025 / Revised: 8 April 2025 / Accepted: 9 April 2025 / Published: 12 April 2025
(This article belongs to the Special Issue Advanced Perspectives on Virus–Host Interactions)

Abstract

Micropeptides (miPEPs), encoded by short open reading frames (sORFs) within various genomic regions, have recently emerged as critical regulators of multiple biological processes. In particular, these small molecules are now increasingly being recognized for their role in modulating viral replication, pathogenesis, and host immune responses. Both host miPEPs and virus-derived miPEPs have been noted for their ability to regulate virus–host interactions through diversified mechanisms such as altering protein stability and modulating protein–protein interactions. Although thousands of sORFs have been annotated as having the potential to encode miPEPs, only a small number have been experimentally validated so far, with some directly linked to virus–host interactions and a small subset associated with immune modulation, indicating that the investigation of miPEPs is still in its infancy. The systematic identification, translational status assessment, in-depth characterization, and functional analysis of a substantial fraction of sORFs encoding miPEPs remain largely underexplored. Further studies are anticipated to uncover the intricate mechanisms underlying virus–host interactions, host immune modulation, and the broader biological functions of miPEPs. This article will review the emerging roles of miPEPs in virus–host interactions and host immunity, and discuss the challenges and future perspectives of miPEP studies.

1. Introduction

Micropeptides (miPEPs), also known as microproteins or small proteins, are generally less than 150 amino acids in length. They are encoded by short open reading frames (sORFs) within diverse regions of the genome that were once thought to be non-coding or lacking functional relevance to protein production [1,2,3]. The miPEP-encoded RNAs include long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), pre-miRNA sequence, coding sequences (CDS), and untranslated regions (UTRs) of canonical messenger RNAs (mRNAs) [1,4,5,6,7,8]. miPEPs are derived not only from intergenic regions but also from introns, alternative reading frames within known genes, and previously unannotated regions of the genome [1,4,9]. They are expressed in both prokaryotic and eukaryotic organisms. Unlike classical bioactive peptides, miPEPs are not cleaved from precursor protein and lack an N-terminal signaling sequence [10]. Therefore, they are released in the cytoplasm immediately after translation [10]. The potential roles for functional peptides encoded by these regions was previously underappreciated, largely due to limitations in genome annotation technologies and the prevailing assumption that non-coding sequences were functionally inert [4]. However, studies of miPEPs have been getting significant attention since some critical examples were identified, such as humanin [11] and myoregulin [12], which demonstrated critical functions in diverse cellular processes. These findings underscored the importance of these small peptides in biological processes.
Recently, large-scale efforts like the ENCODE project have expanded our understanding of genomic coding sequences, revealing the diverse origins of sORF-encoded peptides. Advancements in high-throughput sequencing technologies, ribosome profiling (ribo-seq), and mass spectrometry (MS) have further confirmed that these sORFs are potentially translated into functional miPEPs with noteworthy biological relevance [1,9,13]. Emerging studies have increasingly validated hundreds of miPEPs as key regulators of cellular processes, including host immune responses to infections with pathogens [14]. For instance, a 17-amino-acid miPEP named miPEP155 (P155), encoded by the lncRNA MIR155HG, is highly expressed in inflamed antigen-presenting cells. P155 interacts with heat shock cognate protein 70 to modulate antigen presentation to T cells, thereby playing a crucial role in the initiation of the immune response [15]. Despite these advances, the field is still in its infancy. The experimental identification of sORF translation into biologically active miPEPs remains lacking. Consequently, key areas such as the systematic characterization and elucidation of the roles of miPEPs and underlying mechanisms remain to be determined.
Viruses are obligate intracellular entities with genomes composed of either DNA or RNA. To replicate and propagate, they rely on host cellular machinery [16]. In the context of virus–host interactions, increasing evidence highlights the potential roles of host miPEPs in modulating both host immune responses and viral pathogenesis [17]. On the other hand, the discovery of virus-encoded miPEPs has further expanded the scope of miPEP research, uncovering additional layers of complexity in the interaction between the host immune system and viral infection. However, little information is available about the biogenesis and function of virus-encoded miPEPs. Investigation of the virus-encoded miPEPs could offer valuable insights into viral pathogenesis and provide valuable information for the control of viral diseases. This review highlights recent advances in understanding the roles of miPEPs in virus–host interactions and discusses the challenges and future perspectives in the field of miPEP studies.

2. Biogenesis and Characterization of miPEPs

The biogenesis of miPEPs begins with the transcription of genomic regions containing sORFs, which are typically found within non-coding RNAs (ncRNAs), as well as within the CDS or UTRs of mRNAs. Regulatory elements, such as internal ribosome entry sites (IRES) and N6-methyladenosine (m6A) methylation sites have been shown to mediate miPEP translation. IRES are RNA sequences, typically located in the 5′UTR upstream of the ORF, that facilitate translation without the need for the 5′ cap [5]. IRES elements can also be located within or between ORFs. These elements recruit ribosomes, enabling ribosome assembly and the translation of sORFs into miPEPs. For example, sORFs located in lncRNAs containing IRES elements could be translated into miPEPs [18]. Furthermore, m6A modifications has been shown to enhance the translation of endogenous ncRNAs, particularly circRNAs, and numerous circRNAs with translation potential have been identified [19]. It is also possible that m6A modifications may drive the translation of lncRNAs. These sORFs may be translated into small peptides through mechanisms that bypass traditional translation initiation, such as ribosome reinitiation or upstream open reading frame translation. Unlike full-length proteins, miPEPs are derived from functional sORFs that exist in various RNA molecules, including lncRNAs, circRNAs, pre-microRNAs, lincRNAs, and UTRs of mRNAs. sORFs found in the 5′ and 3′ UTRs are referred to as upstream open reading frames (uORFs) and downstream open reading frames (dORFs), respectively. miPEPs from both uORFs and dORFs have been shown to regulate the translation of the main CDS [20,21]. Additionally, sORFs are found in pseudogenes and intergenic regions. Interestingly, some miPEPs are also derived from DNA in cellular organelles. For example, MOTS-c, humanin, and small humanin-like peptides (SHLP) 1–6 are encoded by sORFs within mitochondrial DNA [22,23,24,25,26,27] (Figure 1).
Several approaches are available to identify sORFs and assess their translation potential into miPEPs. Commonly employed approaches include RNA sequencing (RNA-seq), ribo-seq, MS, and so forth, which are simultaneously complemented by bioinformatics analysis. These methods integrate various techniques, such as predicting ORFs, analyzing translation start elements like IRES, investigating histone modifications, and performing translation omics and proteomics profiling. Readers can refer online database for sORF identification such as sORFs.org [28], SmProt [29], OpenProt [30], ARA-PEPs [31], and so forth. However, these methods are primarily useful for identifying sORFs with the potential to produce miPEPs, rather than directly assessing their translation status and functioning. Functional characterization of sORFs and miPEPs requires experimental validation, including in vitro translation analysis to confirm protein-coding potential, development of specific antibodies for detection, ultrafiltration of cell lysates combined with mass spectrometry analysis, and advanced genetic manipulation techniques, such as CRISPR-Cas9 tagging, to explore their biological functions. However, a very large number of miPEPs encoded by sORFs remain poorly understood. Extensive studies including systematic identification, assessment of translational status, in-depth characterization, and functional analysis of sORFs and miPEPs are required in the future.

3. Roles of miPEPs in Virus–Host Interactions

3.1. Virus–Host Interactions

Virus–host interactions are highly intricate and encompass a vast array of viruses and hosts, ranging from bacteriophages infecting bacteria to human pathogens such as influenza A virus (IAV), human immunodeficiency virus, and severe acute respiratory syndrome coronavirus 2 [16]. Viruses can operate cellular machinery to complete their replication process through interacting with diverse host cell components [17]. These interactions serve two primary purposes: they either directly facilitate key steps in the viral lifecycle, such as entry, intracellular trafficking, genomic replication, gene expression, and the release of viral progenies, or they antagonize cell-intrinsic immune defenses, including type I interferon (type I-IFN)-mediated responses and various cellular pathways like apoptosis, necroptosis, pyroptosis, and ferroptosis [16,17].
The innate immune system is the first line of defense, relying on pattern recognition receptors (PRRs) to detect viral components [16,32]. Activation of these PRRs initiates signaling cascades that result in the production of IFNs and pro-inflammatory cytokines, which mediate innate immunity against viral infection [2,17]. These innate immune responses are further complemented by the adaptive immune system, which provides long-term, virus-specific immunity through the elimination of infected cells by T cells and the production of neutralizing antibodies by B cells [33]. Cellular mechanisms, such as the ubiquitin–proteasome system and autophagy, also play dual roles in terms of regulating viral replication and shaping immune responses [34,35]. Interestingly, viruses such as coronaviruses, flaviviruses, and influenza viruses exhibit species-specific interactions due to their ability to infect a range of hosts, including insects, birds, and mammals [36]. These pathogens have evolved unique mechanisms tailored to each host species likely through specifically binding to their receptor molecules on the surfaces of cells, while host antiviral responses and restriction factors further influence disease outcomes [16]. Differences in host immune responses, including the roles of antiviral restriction factors, can determine whether a viral infection leads to clearance, persistence, or severe pathogenesis in a given species [16].
Additionally, viral infections regulate the expression of numerous host genes [2], including ncRNAs [37,38,39] that may encode miPEPs through sORFs [15,37]. Some viral genomes also contain sORFs encoding miPEPs, which play critical roles in virus–host interactions and viral pathogenesis [40]. Genome-wide high-throughput methods have identified an increasing number of sORF-containing lncRNAs that are potentially involved in immune responses [13], further linking miPEPs to virus–host interplay. miPEPs contribute to the regulation of immune signaling, inflammation, and antiviral defenses by altering protein stability, modulating protein–protein interactions, and so on. On the other hand, viruses have developed sophisticated strategies to evade immune detection [16,41]. These include suppressing IFN signaling, altering antigen presentation, and hijacking host transcriptional and translational machinery to ensure successful replication and survival [41]. The battle between immune activation and viral evasion highlights the dynamic nature of virus–host interplay [41,42]. Understanding these molecular interactions is essential for developing targeted therapeutic strategies and vaccines. Recently, emerging evidence underscores the biological significance of both host and virus-derived miPEPs in virus–host interactions, especially in shaping infection outcomes. This field deserves in-depth and systematic investigation.

3.2. Roles of Host miPEPs in Virus–Host Interactions

Host miPEPs are encoded by sORFs within the different genomic locations. While thousands of these sORFs have been annotated using approaches such as RNA-seq, ribo-seq, and other proteomic techniques, only a limited number of sORFs have been experimentally validated as they are truly translated into miPEPs and play roles in various biological processes. In this review, we only focus on the functional involvement of these miPEPs in virus–host interactions.
miPEPs can participate in various aspects of immune responses to viral infections, from viral recognition to mechanisms underlying the action of effectors [3,20,43]. Virus-induced immune signaling activates host defense pathways, commencing with the detection of viral components such as RNA or DNA by PRRs [16]. This detection triggers signaling cascades that activate transcription factors, including nuclear factor-kappa B (NF-κB) and interferon regulatory factors 3 and 7 [41]. These transcription factors drive the production of numerous cytokines and the expression of antiviral genes, which limit viral replication and enhance immune defenses [44,45,46]. At the same time, when the virus is sensed by the host, expression of miPEPs can also be regulated by the activation of innate immune signaling mediated by the PRRs [2,15,47]. Viral infection induces the production of miPEPs, which, in turn, can modulate the innate immunity and the subsequent shaping of adaptive immune responses. Certain miPEPs act as immune modulators, inhibiting antiviral defenses [2]. For example, miPEPs can regulate various cellular pathways, including autophagy, apoptosis, necroptosis, and ferroptosis, and thereby regulate viral replication [48,49]. Recently, we showed that the miPEP named as PESP promotes IAV replication by enhancing IAV-induced autophagy through upregulation of autophagy related gene 7 (ATG7) [2]. Moreover, it has been reported that miPEP MAVI1, encoded by the ncRNA LINC00998, is downregulated during Vesicular Stomatitis Virus (VSV) infection. MAVI1 inhibits I-IFN signaling by directly binding to the mitochondrial antiviral signaling protein (MAVS) on mitochondria [50]. Additional host miPEPs and their roles in virus–host interactions are summarized in Table 1, and the proposed mechanisms of action of miPEPs, as characterized in virus–host interactions, are shown in Figure 2.

3.3. Roles of Virus-Derived miPEPs in Virus–Host Interactions

Some viral miPEPs derived from viral genomes are also being characterized as critical players in virus–host interplay. For instance, Bombyx mori cytoplasmic polyhedrosis virus (BmCPV) expresses vSP27 from circRNA-vSP27, which induces ROS generation, activates NF-κB signaling, promotes antimicrobial peptide expression, and suppresses BmCPV infection [51]. Similarly, vcircRNA_000048 from BmCPV encodes vSP21, a 21-amino-acid peptide that suppresses viral replication by activating the NF-κB/autophagy pathway via interaction with ubiquitin carboxyl-terminal hydrolase [52]. In Kaposi’s sarcoma-associated herpesvirus (KSHV), T3.0 RNA encodes two miPEPs, vSP-1 (48 amino acids or 48-aa) and vSP-2 (27-aa), which regulate KSHV reactivation and latency. vSP-1 interacts with the replication and transcription activator (RTA), controlling its abundance and activity, while their translation highlights polycistronic sORF expression from misannotated ncRNAs [53,54]. Additionally, ribosome profiling of human cytomegalovirus, KSHV, and Vaccinia virus has revealed numerous sORFs [55], expanding the viral coding repertoire through alternative splicing, RNA editing, and non-canonical translation (please refer Table 1 for the additional information).
Table 1. List of miPEPs directly involved in virus–host interactions.
Table 1. List of miPEPs directly involved in virus–host interactions.
NameSize
(aa)
Origin/SourceVirus–Host
Interactions
Function/MechanismRef.
Host miPEPs involved in virus–host interactions
ORF-67471XR_001139971.3
(lnc557)
Bombyx mori nucleopolyhedrovirus (BmNPV)Not Available[56]
PESP110lncRNA PCBP1-AS1
(human)
IAVEnhances the IAV-induced autophagy by increasing the expression of ATG7.[2]
MIR22HG peptideNAlncRNA MIR22HG
(human)
IAVNot Available[47]
SMIM30/
MAVI1
59LINC00998VSVEndoplasmic reticulum–localized microprotein that suppresses antiviral innate immune response by targeting MAVS on mitochondria.[50]
Virus-encoded miPEPs involved in virus–host interactions
vsp2121vcircRNA_000048
(silkworm)
BmCPVAttenuates the viral replication.[40]
vSP27NAcircular RNA
(circRNA-vSP27)
BmCPVSuppresses BmCPV infection.[51]
VSP5959S10 dsRNA genomeBmCPVNegatively regulates of viral replication.[57]
PB1-F287–90Influenza A/PR/8/34 virusIAVMitochondria localized miPEP that induces apoptosis in host cells.[58]
vSP-148T3.0 RNA from KSHVKSHVPrecisely control of RTA abundance and activity in KSHV reactivation and initiates the establishment of latency of the KSHV.[53,54]
vSP-227T3.0 RNA from KSHVKSHVNot Available[53,54]

3.4. Roles of Host-Derived miPEPs in Physiological and Pathological Processes: Potential Roles in Virus–Host Interactions

Over the past decade, there have been an increasing number of studies indicating that miPEPs play critical roles in promoting or suppressing tumor growth [59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74] and other physiological and pathological processes, including apoptosis [26,27,49,75,76], stress response [49], and inflammation [43,77,78,79]. In particular, the functioning of miPEPs in the occurrence and development of tumors has attracted growing interest [6,75]. Although the role of miPEPs in the context of virus–host interactions remains largely unknown, their function in other cellular processes suggests that they are potentially involved in virus–host interactions. For example, several IAV proteins induce mitophagy [80], autophagy [81], and ferroptosis [82] to inhibit MAVS-mediated antiviral signaling [80,81,82]. By suppressing the I-IFN response, these processes facilitate viral replication and immune evasion. Therefore, miPEPs previously characterized in various cellular pathways such as mitophagy, autophagy, apoptosis, and some cancer-related signaling may also play a key role in virus–host interactions. Interestingly, several miPEPs have been shown to interact directly with MAVS [50,83]. Some of these miPEPs have been shown to modulate key antiviral signaling pathways, including STAT3 and NLRP3 inflammasome signaling [43,79,84]. Table 2 lists some representative miPEPs involved in these cellular processes.
Table 2. miPEPs potentially involved in virus–host interactions.
Table 2. miPEPs potentially involved in virus–host interactions.
Name Size (aa)Origin/SourceFunction/MechanismRef.
ASRPS60LINC00908miPEPs regulate innate or adaptive immunity.[15,84,85,86,87]
P15517lncRNA MIR155HG
miPEP3144pri-miRNA-31
Stmp1/Mm4747lncRNA 1810058I24RikActivates the NLRP3 inflammasome pathway[43,77,78,79,88]
SHLP226mitochondrial 16S rRNA geneRegulate apoptosis.[26,27,49,75,76]
PIGBOS54PIGB opposite strand 1
FORCP79LINC00675
YY1BM21LINC00278
AC115619-22aa22lncRNA AC115619Regulates autophagy[48]
PINT87aa87LINC-PINTRegulates mitophagy[89]
PACMP44lncRNA CTD-2256P15.2Modulates DNA damage response.[90]

4. Challenges and Future Perspectives of miPEP Study

Despite the exciting potential of miPEPs in virus–host interactions, several challenges hinder their study. One major difficulty lies in detecting and characterizing these small peptides due to their typically low expression levels and small sizes [91,92,93,94]. Conventional proteomics methods often struggle to differentiate miPEPs from background noise, necessitating more sensitive approaches such as ribo-seq and MS with enhanced detection capabilities [95,96,97,98]. Immunoblotting remains a traditional and straightforward technique for detecting proteins, including small peptides. However, generating specific antibodies against miPEPs presents significant hurdles. Peptides containing transmembrane domains may restrict the availability of epitopes suitable for antibody production, complicating detection and validation efforts. Moreover, the lack of comprehensive databases and annotation for miPEPs further challenges their identification and functional characterization.
Another challenge is the dynamic nature of their expression, which varies with cellular contexts, stress conditions, and viral infections [2,15,75]. Understanding how miPEPs are regulated during infections requires integrative transcriptomic and proteomic analyses, as well as functional validation in relevant biological models. Furthermore, while in vitro systems provide valuable insights, studying miPEPs in complex tissue environments is essential for understanding their roles in vivo.
Addressing these challenges will require advancements in detection methodologies, computational prediction tools, and functional assays. Overcoming these obstacles will not only improve our understanding of miPEPs in viral infections but also open new avenues for therapeutic interventions targeting these small yet potentially influential molecules.
Although progress has been made in understanding the role of miPEPs in virus–host interactions, the functional relevance of these small peptides in viral pathogenesis still remains elusive. This is an area worth exploring further. The fact that hundreds of lncRNAs, each containing lots of sORFs, are polyadenylated, localized in the cytoplasm, and associated with ribosomes further supports the notion that the translation of miPEPs may be a widespread phenomenon [99,100,101]. However, the extent to which these miPEPs contribute to biological processes needs to be further determined.
One promising avenue for future research is the systematic identification and characterization of the miPEPs that influence viral replication and immune evasion. Recent studies have demonstrated that viral infections, including IAV, can alter sites of translation initiation, sometimes leading to the production of novel immune epitopes [102]. Ribo-seq and translation initiation mapping in infected cells could help uncover miPEPs that modulate antiviral responses. Since IAV infection is known to induce mitophagy, autophagy, and ferroptosis while inhibiting MAVS-mediated antiviral responses, investigating whether miPEPs interact with these pathways could provide new insights into viral pathogenesis and host defense mechanisms [80,81,82].
Additionally, expanding research beyond in vitro cell culture systems is crucial. While virus–host interactions are often studied in single-cell models, infections occur in complex tissue environments that include immune and non-immune cells, extracellular matrix components, and a dynamic immune microenvironment. Advanced methodologies such as spatial transcriptomics and single-cell proteomics could be leveraged to profile miPEP expression and function in infected tissues. This would provide a more comprehensive understanding of their roles in vivo.
Ultimately, uncovering the functional significance of miPEPs in virus–host interactions could open new avenues for antiviral therapeutics. By identifying miPEPs that regulate key immune pathways, researchers may discover novel targets for intervention. The integration of high-throughput sequencing, proteomics, and advanced computational analyses will be essential in deciphering the full impact of miPEPs on viral infections and host immunity. As this field evolves, a deeper understanding of miPEPs may transform our approach to antiviral strategies and immune modulation.

5. Summary

miPEPs are promising yet understudied molecules implicated in various biological processes. Increasing reports have shown that they play critical roles in virus–host interactions, especially in the regulation of immune responses. However, direct evidence remains limited, emphasizing the field’s early stage. Advancing technologies like ribo-seq, proteomics, and spatial transcriptomics, coupled with experimental validation, will be key to uncovering their functions in viral infection. Moreover, future research should explore miPEPs as therapeutic targets, paving a way for the development of new antiviral strategies. In summary, better understanding of their roles in virus–host interactions could deepen our knowledge of viral pathogenesis and drive targeted interventions for viral infectious diseases.

Author Contributions

Conceptualization, J.-L.C. and K.R.R.; systematic literature review, H.S., R.G. and T.T.; writing—original draft preparation, K.R.R. and H.S.; review and editing, K.R.R. and J.-L.C.; supervision, critical comments and suggestions, and manuscript revision, J.-L.C.; and funding acquisition, J.-L.C. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (U23A20235 and 32030110) and the Fujian Agriculture and Forestry University Science and Technology Innovation Fund (KFB23094).

Institutional Review Board Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Acknowledgments

We acknowledge all the members of Chen’s laboratory who involved in the fruitful discussions on the literature review.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
HSP90Heat shock protein 90
NLRP3NOD-like receptor family Pyrin domain-containing protein 3
LincRNAsLong intronic non-coding RNAs
CRISPR-Cas9Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated protein 9

References

  1. Couso, J.P.; Patraquim, P. Classification and function of small open reading frames. Nat. Rev. Mol. Cell Biol. 2017, 18, 575–589. [Google Scholar] [CrossRef] [PubMed]
  2. Chi, X.; Huang, G.; Wang, L.; Zhang, X.; Liu, J.; Yin, Z.; Guo, G.; Chen, Y.; Wang, S.; Chen, J.L. A small protein encoded by PCBP1-AS1 is identified as a key regulator of influenza virus replication via enhancing autophagy. PLoS Pathog. 2024, 20, e1012461. [Google Scholar] [CrossRef] [PubMed]
  3. Dong, X.; Zhang, K.; Xun, C.; Chu, T.; Liang, S.; Zeng, Y.; Liu, Z. Small Open Reading Frame-Encoded Micro-Peptides: An Emerging Protein World. Int. J. Mol. Sci. 2023, 24, 10562. [Google Scholar] [CrossRef] [PubMed]
  4. Patraquim, P.; Magny, E.G.; Pueyo, J.I.; Platero, A.I.; Couso, J.P. Translation and natural selection of micropeptides from long non-canonical RNAs. Nat. Commun. 2022, 13, 6515. [Google Scholar] [CrossRef]
  5. Ryczek, N.; Łyś, A.; Makałowska, I. The Functional Meaning of 5′UTR in Protein-Coding Genes. Int. J. Mol. Sci. 2023, 24, 2976. [Google Scholar] [CrossRef]
  6. Tornesello, A.L.; Cerasuolo, A.; Starita, N.; Amiranda, S.; Cimmino, T.P.; Bonelli, P.; Tuccillo, F.M.; Buonaguro, F.M.; Buonaguro, L.; Tornesello, M.L. Emerging role of endogenous peptides encoded by non-coding RNAs in cancer biology. Noncoding RNA Res. 2025, 10, 231–241. [Google Scholar] [CrossRef]
  7. Kang, M.; Tang, B.; Li, J.; Zhou, Z.; Liu, K.; Wang, R.; Jiang, Z.; Bi, F.; Patrick, D.; Kim, D.; et al. Correction: Identification of miPEP133 as a novel tumor-suppressor microprotein encoded by miR-34a pri-miRNA. Mol. Cancer 2024, 23, 195. [Google Scholar] [CrossRef]
  8. Zhou, X.; Wu, X.; Lai, K.; Zhou, R.; Chen, Z.; Yang, Z.; Gao, X. Discovery of the hidden coding information in cancers: Mechanisms and biological functions. Int. J. Cancer 2023, 153, 20–32. [Google Scholar] [CrossRef]
  9. Olexiouk, V.; Crappé, J.; Verbruggen, S.; Verhegen, K.; Martens, L.; Menschaert, G. sORFs.org: A repository of small ORFs identified by ribosome profiling. Nucleic Acids Res. 2016, 44, D324–D329. [Google Scholar] [CrossRef]
  10. Erokhina, T.N.; Ryazantsev, D.Y.; Zavriev, S.K.; Morozov, S.Y. Regulatory miPEP Open Reading Frames Contained in the Primary Transcripts of microRNAs. Int. J. Mol. Sci. 2023, 24, 2114. [Google Scholar] [CrossRef]
  11. Hashimoto, Y.; Niikura, T.; Tajima, H.; Yasukawa, T.; Sudo, H.; Ito, Y.; Kita, Y.; Kawasumi, M.; Kouyama, K.; Doyu, M.; et al. A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer’s disease genes and Abeta. Proc. Natl. Acad. Sci. USA 2001, 98, 6336–6341. [Google Scholar] [CrossRef] [PubMed]
  12. Anderson, D.M.; Anderson, K.M.; Chang, C.L.; Makarewich, C.A.; Nelson, B.R.; McAnally, J.R.; Kasaragod, P.; Shelton, J.M.; Liou, J.; Bassel-Duby, R.; et al. A micropeptide encoded by a putative long noncoding RNA regulates muscle performance. Cell 2015, 160, 595–606. [Google Scholar] [CrossRef] [PubMed]
  13. Zhu, M.; Gribskov, M. MiPepid: MicroPeptide identification tool using machine learning. BMC Bioinform. 2019, 20, 559. [Google Scholar] [CrossRef]
  14. Xiao, Y.; Ren, Y.; Hu, W.; Paliouras, A.R.; Zhang, W.; Zhong, L.; Yang, K.; Su, L.; Wang, P.; Li, Y.; et al. Long non-coding RNA-encoded micropeptides: Functions, mechanisms and implications. Cell Death Discov. 2024, 10, 450. [Google Scholar] [CrossRef]
  15. Niu, L.; Lou, F.; Sun, Y.; Sun, L.; Cai, X.; Liu, Z.; Zhou, H.; Wang, H.; Wang, Z.; Bai, J.; et al. A micropeptide encoded by lncRNA MIR155HG suppresses autoimmune inflammation via modulating antigen presentation. Sci. Adv. 2020, 6, eaaz2059. [Google Scholar] [CrossRef]
  16. Rai, K.R.; Shrestha, P.; Yang, B.; Chen, Y.; Liu, S.; Maarouf, M.; Chen, J.L. Acute Infection of Viral Pathogens and Their Innate Immune Escape. Front. Microbiol. 2021, 12, 672026. [Google Scholar] [CrossRef]
  17. Strumillo, S.T.; Kartavykh, D.; de Carvalho, F.F., Jr.; Cruz, N.C.; de Souza Teodoro, A.C.; Sobhie Diaz, R.; Curcio, M.F. Host-virus interaction and viral evasion. Cell Biol. Int. 2021, 45, 1124–1147. [Google Scholar] [CrossRef]
  18. Zhao, J.; Li, Y.; Wang, C.; Zhang, H.; Zhang, H.; Jiang, B.; Guo, X.; Song, X. IRESbase: A Comprehensive Database of Experimentally Validated Internal Ribosome Entry Sites. Genom. Proteom. Bioinform. 2020, 18, 129–139. [Google Scholar] [CrossRef]
  19. Tang, M.; Lv, Y. The Role of N(6)-Methyladenosine Modified Circular RNA in Pathophysiological Processes. Int. J. Biol. Sci. 2021, 17, 2262–2277. [Google Scholar] [CrossRef]
  20. Wright, B.W.; Yi, Z.; Weissman, J.S.; Chen, J. The dark proteome: Translation from noncanonical open reading frames. Trends Cell Biol. 2022, 32, 243–258. [Google Scholar] [CrossRef]
  21. Frei, Y.; Immarigeon, C.; Revel, M.; Karch, F.; Maeda, R.K. Upstream open reading frames repress the translation from the iab-8 RNA. PLoS Genet. 2024, 20, e1011214. [Google Scholar] [CrossRef] [PubMed]
  22. Lee, C.; Zeng, J.; Drew, B.G.; Sallam, T.; Martin-Montalvo, A.; Wan, J.; Kim, S.J.; Mehta, H.; Hevener, A.L.; de Cabo, R.; et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. 2015, 21, 443–454. [Google Scholar] [CrossRef] [PubMed]
  23. Merry, T.L.; Chan, A.; Woodhead, J.S.T.; Reynolds, J.C.; Kumagai, H.; Kim, S.J.; Lee, C. Mitochondrial-derived peptides in energy metabolism. Am. J. Physiol. Endocrinol. Metab. 2020, 319, E659–E666. [Google Scholar] [CrossRef] [PubMed]
  24. Lee, C.; Yen, K.; Cohen, P. Humanin: A harbinger of mitochondrial-derived peptides? Trends Endocrinol. Metab. 2013, 24, 222–228. [Google Scholar] [CrossRef]
  25. Yen, K.; Mehta, H.H.; Kim, S.J.; Lue, Y.; Hoang, J.; Guerrero, N.; Port, J.; Bi, Q.; Navarrete, G.; Brandhorst, S.; et al. The mitochondrial derived peptide humanin is a regulator of lifespan and healthspan. Aging 2020, 12, 11185–11199. [Google Scholar] [CrossRef]
  26. Cobb, L.J.; Lee, C.; Xiao, J.; Yen, K.; Wong, R.G.; Nakamura, H.K.; Mehta, H.H.; Gao, Q.; Ashur, C.; Huffman, D.M.; et al. Naturally occurring mitochondrial-derived peptides are age-dependent regulators of apoptosis, insulin sensitivity, and inflammatory markers. Aging 2016, 8, 796–809. [Google Scholar] [CrossRef]
  27. Kim, S.K.; Tran, L.T.; NamKoong, C.; Choi, H.J.; Chun, H.J.; Lee, Y.H.; Cheon, M.; Chung, C.; Hwang, J.; Lim, H.H.; et al. Author Correction: Mitochondria-derived peptide SHLP2 regulates energy homeostasis through the activation of hypothalamic neurons. Nat. Commun. 2023, 14, 4995. [Google Scholar] [CrossRef]
  28. Olexiouk, V.; Van Criekinge, W.; Menschaert, G. An update on sORFs.org: A repository of small ORFs identified by ribosome profiling. Nucleic Acids Res. 2018, 46, D497–D502. [Google Scholar] [CrossRef]
  29. Hao, Y.; Zhang, L.; Niu, Y.; Cai, T.; Luo, J.; He, S.; Zhang, B.; Zhang, D.; Qin, Y.; Yang, F.; et al. SmProt: A database of small proteins encoded by annotated coding and non-coding RNA loci. Brief. Bioinform. 2018, 19, 636–643. [Google Scholar] [CrossRef]
  30. Brunet, M.A.; Lucier, J.F.; Levesque, M.; Leblanc, S.; Jacques, J.F.; Al-Saedi, H.R.H.; Guilloy, N.; Grenier, F.; Avino, M.; Fournier, I.; et al. OpenProt 2021: Deeper functional annotation of the coding potential of eukaryotic genomes. Nucleic Acids Res. 2021, 49, D380–D388. [Google Scholar] [CrossRef]
  31. Hazarika, R.R.; De Coninck, B.; Yamamoto, L.R.; Martin, L.R.; Cammue, B.P.; van Noort, V. ARA-PEPs: A repository of putative sORF-encoded peptides in Arabidopsis thaliana. BMC Bioinform. 2017, 18, 37. [Google Scholar] [CrossRef] [PubMed]
  32. Honda, K.; Taniguchi, T. IRFs: Master regulators of signalling by Toll-like receptors and cytosolic pattern-recognition receptors. Nat. Rev. Immunol. 2006, 6, 644–658. [Google Scholar] [CrossRef] [PubMed]
  33. Sette, A.; Crotty, S. Adaptive immunity to SARS-CoV-2 and COVID-19. Cell 2021, 184, 861–880. [Google Scholar] [CrossRef] [PubMed]
  34. Park, E.S.; Dezhbord, M.; Lee, A.R.; Kim, K.H. The Roles of Ubiquitination in Pathogenesis of Influenza Virus Infection. Int. J. Mol. Sci. 2022, 23, 4593. [Google Scholar] [CrossRef]
  35. Resnik, R.; Lopez Mingorance, F.; Rivera, F.; Mitchell, F.; Gonzalez, C.D.; Vaccaro, M.I. Autophagy in Inflammatory Response against SARS-CoV-2. Int. J. Mol. Sci. 2023, 24, 4928. [Google Scholar] [CrossRef]
  36. Lamy-Besnier, Q.; Brancotte, B.; Ménager, H.; Debarbieux, L. Viral Host Range database, an online tool for recording, analyzing and disseminating virus-host interactions. Bioinformatics 2021, 37, 2798–2801. [Google Scholar] [CrossRef]
  37. Rai, K.R.; Liao, Y.; Cai, M.; Qiu, H.; Wen, F.; Peng, M.; Wang, S.; Liu, S.; Guo, G.; Chi, X.; et al. MIR155HG Plays a Bivalent Role in Regulating Innate Antiviral Immunity by Encoding Long Noncoding RNA-155 and microRNA-155-5p. mBio 2022, 13, e0251022. [Google Scholar] [CrossRef]
  38. Ouyang, J.; Zhu, X.; Chen, Y.; Wei, H.; Chen, Q.; Chi, X.; Qi, B.; Zhang, L.; Zhao, Y.; Gao, G.F.; et al. NRAV, a long noncoding RNA, modulates antiviral responses through suppression of interferon-stimulated gene transcription. Cell Host Microbe 2014, 16, 616–626. [Google Scholar] [CrossRef]
  39. Chen, B.; Guo, G.; Wang, G.; Zhu, Q.; Wang, L.; Shi, W.; Wang, S.; Chen, Y.; Chi, X.; Wen, F.; et al. ATG7/GAPLINC/IRF3 axis plays a critical role in regulating pathogenesis of influenza A virus. PLoS Pathog. 2024, 20, e1011958. [Google Scholar] [CrossRef]
  40. Zhang, Y.; Zhu, M.; Zhang, X.; Dai, K.; Liang, Z.; Pan, J.; Zhang, Z.; Cao, M.; Xue, R.; Cao, G.; et al. Micropeptide vsp21 translated by Reovirus circular RNA 000048 attenuates viral replication. Int. J. Biol. Macromol. 2022, 209 Pt A, 1179–1187. [Google Scholar] [CrossRef]
  41. Maarouf, M.; Rai, K.R.; Goraya, M.U.; Chen, J.L. Immune Ecosystem of Virus-Infected Host Tissues. Int. J. Mol. Sci. 2018, 19, 1379. [Google Scholar] [CrossRef] [PubMed]
  42. Sakowski, E.G.; Arora-Williams, K.; Tian, F.; Zayed, A.A.; Zablocki, O.; Sullivan, M.B.; Preheim, S.P. Interaction dynamics and virus-host range for estuarine actinophages captured by epicPCR. Nat. Microbiol. 2021, 6, 630–642. [Google Scholar] [CrossRef] [PubMed]
  43. Zheng, X.; Wang, M.; Liu, S.; Chen, H.; Li, Y.; Yuan, F.; Yang, L.; Qiu, S.; Wang, H.; Xie, Z.; et al. A lncRNA-encoded mitochondrial micropeptide exacerbates microglia-mediated neuroinflammation in retinal ischemia/reperfusion injury. Cell Death Dis. 2023, 14, 126. [Google Scholar] [CrossRef]
  44. Kane, M.; Zang, T.M.; Rihn, S.J.; Zhang, F.; Kueck, T.; Alim, M.; Schoggins, J.; Rice, C.M.; Wilson, S.J.; Bieniasz, P.D. Identification of Interferon-Stimulated Genes with Antiretroviral Activity. Cell Host Microbe 2016, 20, 392–405. [Google Scholar] [CrossRef]
  45. Rai, K.R.; Chen, B.; Zhao, Z.; Chen, Y.; Hu, J.; Liu, S.; Maarouf, M.; Li, Y.; Xiao, M.; Liao, Y.; et al. Robust expression of p27Kip1 induced by viral infection is critical for antiviral innate immunity. Cell Microbiol. 2020, 22, e13242. [Google Scholar] [CrossRef]
  46. Li, F.; Chen, Y.; Zhang, Z.; Ouyang, J.; Wang, Y.; Yan, R.; Huang, S.; Gao, G.F.; Guo, G.; Chen, J.L. Robust expression of vault RNAs induced by influenza A virus plays a critical role in suppression of PKR-mediated innate immunity. Nucleic Acids Res. 2015, 43, 10321–10337. [Google Scholar] [CrossRef] [PubMed]
  47. Razooky, B.S.; Obermayer, B.; O’May, J.B.; Tarakhovsky, A. Viral Infection Identifies Micropeptides Differentially Regulated in smORF-Containing lncRNAs. Genes 2017, 8, 206. [Google Scholar] [CrossRef]
  48. Zhang, Q.; Wei, T.; Yan, L.; Zhu, S.; Jin, W.; Bai, Y.; Zeng, Y.; Zhang, X.; Yin, Z.; Yang, J.; et al. Hypoxia-Responsive lncRNA AC115619 Encodes a Micropeptide That Suppresses m6A Modifications and Hepatocellular Carcinoma Progression. Cancer Res. 2023, 83, 2496–2512. [Google Scholar] [CrossRef]
  49. Chu, Q.; Martinez, T.F.; Novak, S.W.; Donaldson, C.J.; Tan, D.; Vaughan, J.M.; Chang, T.; Diedrich, J.K.; Andrade, L.; Kim, A.; et al. Regulation of the ER stress response by a mitochondrial microprotein. Nat. Commun. 2019, 10, 4883. [Google Scholar] [CrossRef]
  50. Shi, T.T.; Huang, Y.; Li, Y.; Dai, X.L.; He, Y.H.; Ding, J.C.; Ran, T.; Shi, Y.; Yuan, Q.; Li, W.J.; et al. MAVI1, an endoplasmic reticulum-localized microprotein, suppresses antiviral innate immune response by targeting MAVS on mitochondrion. Sci. Adv. 2023, 9, eadg7053. [Google Scholar] [CrossRef]
  51. Zhang, Y.; Zhang, X.; Dai, K.; Zhu, M.; Liang, Z.; Pan, J.; Zhang, Z.; Xue, R.; Cao, G.; Hu, X.; et al. Bombyx mori Akirin hijacks a viral peptide vSP27 encoded by BmCPV circRNA and activates the ROS-NF-κB pathway against viral infection. Int. J. Biol. Macromol. 2022, 194, 223–232. [Google Scholar] [CrossRef] [PubMed]
  52. Zhang, Y.; Zhu, M.; Pan, J.; Qiu, Q.; Tong, X.; Hu, X.; Gong, C. BmCPV replication is suppressed by the activation of the NF-κB/autophagy pathway through the interaction of vsp21 translated by vcircRNA_000048 with ubiquitin carboxyl-terminal hydrolase. Insect Biochem. Mol. Biol. 2023, 156, 103947. [Google Scholar] [CrossRef] [PubMed]
  53. Jaber, T.; Yuan, Y. A virally encoded small peptide regulates RTA stability and facilitates Kaposi’s sarcoma-associated herpesvirus lytic replication. J. Virol. 2013, 87, 3461–3470. [Google Scholar] [CrossRef] [PubMed]
  54. Xu, L.; Yuan, Y. Two microPeptides are translated from a KSHV polycistronic RNA in human cells by leaky scanning mechanism. Biochem. Biophys. Res. Commun. 2020, 522, 568–573. [Google Scholar] [CrossRef]
  55. Yang, Z.; Cao, S.; Martens, C.A.; Porcella, S.F.; Xie, Z.; Ma, M.; Shen, B.; Moss, B. Deciphering poxvirus gene expression by RNA sequencing and ribosome profiling. J. Virol. 2015, 89, 6874–6886. [Google Scholar] [CrossRef]
  56. Lin, S.; Shen, Z.Y.; Wang, M.D.; Zhou, X.M.; Xu, T.; Jiao, X.H.; Wang, L.L.; Guo, X.J.; Wu, P. Lnc557 promotes Bombyx mori nucleopolyhedrovirus replication by interacting with BmELAVL1 to enhance its stability and expression. Pestic. Biochem. Physiol. 2024, 204, 106046. [Google Scholar] [CrossRef]
  57. Cao, M.; Qiu, Q.; Zhang, X.; Zhang, W.; Shen, Z.; Ma, C.; Zhu, M.; Pan, J.; Tong, X.; Cao, G.; et al. Identification and characterization of a novel small viral peptide (VSP59) encoded by Bombyx mori cypovirus (BmCPV) that negatively regulates viral replication. Microbiol. Spectr. 2024, 12, e0082624. [Google Scholar] [CrossRef]
  58. Zamarin, D.; García-Sastre, A.; Xiao, X.; Wang, R.; Palese, P. Influenza virus PB1-F2 protein induces cell death through mitochondrial ANT3 and VDAC1. PLoS Pathog. 2005, 1, e4. [Google Scholar] [CrossRef]
  59. Zheng, W.; Guo, Y.; Zhang, G.; Bai, J.; Song, Y.; Song, X.; Zhu, Q.; Bao, X.; Wu, G.; Zhang, C. Peptide encoded by lncRNA BVES-AS1 promotes cell viability, migration, and invasion in colorectal cancer cells via the SRC/mTOR signaling pathway. PLoS ONE 2023, 18, e0287133. [Google Scholar] [CrossRef]
  60. Li, M.; Li, X.; Zhang, Y.; Wu, H.; Zhou, H.; Ding, X.; Zhang, X.; Jin, X.; Wang, Y.; Yin, X.; et al. Micropeptide MIAC Inhibits HNSCC Progression by Interacting with Aquaporin 2. J. Am. Chem. Soc. 2020, 142, 6708–6716. [Google Scholar] [CrossRef]
  61. Huang, J.Z.; Chen, M.; Chen, D.; Gao, X.C.; Zhu, S.; Huang, H.; Hu, M.; Zhu, H.; Yan, G.R. A Peptide Encoded by a Putative lncRNA HOXB-AS3 Suppresses Colon Cancer Growth. Mol. Cell 2017, 68, 171–184.e6. [Google Scholar] [CrossRef] [PubMed]
  62. Wang, L.; Fan, J.; Han, L.; Qi, H.; Wang, Y.; Wang, H.; Chen, S.; Du, L.; Li, S.; Zhang, Y.; et al. The micropeptide LEMP plays an evolutionarily conserved role in myogenesis. Cell Death Dis. 2020, 11, 357. [Google Scholar] [CrossRef] [PubMed]
  63. Szafron, L.A.; Iwanicka-Nowicka, R.; Podgorska, A.; Bonna, A.M.; Sobiczewski, P.; Kupryjanczyk, J.; Szafron, L.M. The Clinical Significance of CRNDE Gene Methylation, Polymorphisms, and CRNDEP Micropeptide Expression in Ovarian Tumors. Int. J. Mol. Sci. 2024, 25, 7531. [Google Scholar] [CrossRef] [PubMed]
  64. Pei, H.; Dai, Y.; Yu, Y.; Tang, J.; Cao, Z.; Zhang, Y.; Li, B.; Nie, J.; Hei, T.K.; Zhou, G. The Tumorigenic Effect of lncRNA AFAP1-AS1 is Mediated by Translated Peptide ATMLP Under the Control of m(6) A Methylation. Adv. Sci. 2023, 10, e2300314. [Google Scholar] [CrossRef]
  65. Xu, W.; Deng, B.; Lin, P.; Liu, C.; Li, B.; Huang, Q.; Zhou, H.; Yang, J.; Qu, L. Ribosome profiling analysis identified a KRAS-interacting microprotein that represses oncogenic signaling in hepatocellular carcinoma cells. Sci. China Life Sci. 2020, 63, 529–542. [Google Scholar] [CrossRef]
  66. Pan, J.; Liu, M.; Duan, X.; Wang, D. A short peptide LINC00665_18aa encoded by lncRNA LINC00665 suppresses the proliferation and migration of osteosarcoma cells through the regulation of the CREB1/RPS6KA3 interaction. PLoS ONE 2023, 18, e0286422. [Google Scholar] [CrossRef]
  67. Guo, B.; Wu, S.; Zhu, X.; Zhang, L.; Deng, J.; Li, F.; Wang, Y.; Zhang, S.; Wu, R.; Lu, J.; et al. Micropeptide CIP2A-BP encoded by LINC00665 inhibits triple-negative breast cancer progression. Embo J. 2020, 39, e102190. [Google Scholar] [CrossRef]
  68. Polenkowski, M.; Burbano de Lara, S.; Allister, A.B.; Nguyen, T.N.Q.; Tamura, T.; Tran, D.D.H. Identification of Novel Micropeptides Derived from Hepatocellular Carcinoma-Specific Long Noncoding RNA. Int. J. Mol. Sci. 2021, 23, 58. [Google Scholar] [CrossRef]
  69. Matsumoto, A.; Pasut, A.; Matsumoto, M.; Yamashita, R.; Fung, J.; Monteleone, E.; Saghatelian, A.; Nakayama, K.I.; Clohessy, J.G.; Pandolfi, P.P. mTORC1 and muscle regeneration are regulated by the LINC00961-encoded SPAR polypeptide. Nature 2017, 541, 228–232. [Google Scholar] [CrossRef]
  70. Ge, Q.; Jia, D.; Cen, D.; Qi, Y.; Shi, C.; Li, J.; Sang, L.; Yang, L.J.; He, J.; Lin, A.; et al. Micropeptide ASAP encoded by LINC00467 promotes colorectal cancer progression by directly modulating ATP synthase activity. J. Clin. Investig. 2021, 131, e152911. [Google Scholar] [CrossRef]
  71. Meng, K.; Lu, S.; Li, Y.Y.; Hu, L.L.; Zhang, J.; Cao, Y.; Wang, Y.; Zhang, C.Z.; He, Q.Y. LINC00493-encoded microprotein SMIM26 exerts anti-metastatic activity in renal cell carcinoma. EMBO Rep. 2023, 24, e56282. [Google Scholar] [CrossRef] [PubMed]
  72. Meng, N.; Chen, M.; Chen, D.; Chen, X.H.; Wang, J.Z.; Zhu, S.; He, Y.T.; Zhang, X.L.; Lu, R.X.; Yan, G.R. Small Protein Hidden in lncRNA LOC90024 Promotes “Cancerous” RNA Splicing and Tumorigenesis. Adv. Sci. 2020, 7, 1903233. [Google Scholar] [CrossRef] [PubMed]
  73. Li, F.; Cai, Y.; Deng, S.; Yang, L.; Liu, N.; Chang, X.; Jing, L.; Zhou, Y.; Li, H. A peptide CORO1C-47aa encoded by the circular noncoding RNA circ-0000437 functions as a negative regulator in endometrium tumor angiogenesis. J. Biol. Chem. 2021, 297, 101182. [Google Scholar] [CrossRef] [PubMed]
  74. Zheng, X.; Chen, L.; Zhou, Y.; Wang, Q.; Zheng, Z.; Xu, B.; Wu, C.; Zhou, Q.; Hu, W.; Wu, C.; et al. A novel protein encoded by a circular RNA circPPP1R12A promotes tumor pathogenesis and metastasis of colon cancer via Hippo-YAP signaling. Mol. Cancer 2019, 18, 47. [Google Scholar] [CrossRef]
  75. Li, X.L.; Pongor, L.; Tang, W.; Das, S.; Muys, B.R.; Jones, M.F.; Lazar, S.B.; Dangelmaier, E.A.; Hartford, C.C.; Grammatikakis, I.; et al. A small protein encoded by a putative lncRNA regulates apoptosis and tumorigenicity in human colorectal cancer cells. eLife 2020, 9, e53734. [Google Scholar] [CrossRef]
  76. Wu, S.; Zhang, L.; Deng, J.; Guo, B.; Li, F.; Wang, Y.; Wu, R.; Zhang, S.; Lu, J.; Zhou, Y. A Novel Micropeptide Encoded by Y-Linked LINC00278 Links Cigarette Smoking and AR Signaling in Male Esophageal Squamous Cell Carcinoma. Cancer Res. 2020, 80, 2790–2803. [Google Scholar] [CrossRef]
  77. Xie, C.; Wang, F.-Y.; Sang, Y.; Chen, B.; Huang, J.-H.; He, F.-J.; Li, H.; Zhu, Y.; Liu, X.; Zhuang, S.-M.; et al. Mitochondrial Micropeptide STMP1 Enhances Mitochondrial Fission to Promote Tumor Metastasis. Cancer Res. 2022, 82, 2431–2443. [Google Scholar] [CrossRef]
  78. Zheng, X.; Guo, Y.; Zhang, R.; Chen, H.; Liu, S.; Qiu, S.; Xiang, M. The mitochondrial micropeptide Stmp1 promotes retinal cell differentiation. Biochem. Biophys. Res. Commun. 2022, 636 Pt 2, 79–86. [Google Scholar] [CrossRef]
  79. Bhatta, A.; Atianand, M.; Jiang, Z.; Crabtree, J.; Blin, J.; Fitzgerald, K.A. A Mitochondrial Micropeptide Is Required for Activation of the Nlrp3 Inflammasome. J. Immunol. 2020, 204, 428–437. [Google Scholar] [CrossRef]
  80. Zhang, B.; Xu, S.; Liu, M.; Wei, Y.; Wang, Q.; Shen, W.; Lei, C.Q.; Zhu, Q. The nucleoprotein of influenza A virus inhibits the innate immune response by inducing mitophagy. Autophagy 2023, 19, 1916–1933. [Google Scholar] [CrossRef]
  81. Zeng, Y.; Xu, S.; Wei, Y.; Zhang, X.; Wang, Q.; Jia, Y.; Wang, W.; Han, L.; Chen, Z.; Wang, Z.; et al. The PB1 protein of influenza A virus inhibits the innate immune response by targeting MAVS for NBR1-mediated selective autophagic degradation. PLoS Pathog. 2021, 17, e1009300. [Google Scholar] [CrossRef] [PubMed]
  82. Ouyang, A.; Chen, T.; Feng, Y.; Zou, J.; Tu, S.; Jiang, M.; Sun, H.; Zhou, H. The Hemagglutinin of Influenza A Virus Induces Ferroptosis to Facilitate Viral Replication. Adv. Sci. 2024, 11, e2404365. [Google Scholar] [CrossRef] [PubMed]
  83. Varga, Z.T.; Grant, A.; Manicassamy, B.; Palese, P. Influenza virus protein PB1-F2 inhibits the induction of type I interferon by binding to MAVS and decreasing mitochondrial membrane potential. J. Virol. 2012, 86, 8359–8366. [Google Scholar] [CrossRef] [PubMed]
  84. Wang, Y.; Wu, S.; Zhu, X.; Zhang, L.; Deng, J.; Li, F.; Guo, B.; Zhang, S.; Wu, R.; Zhang, Z.; et al. LncRNA-encoded polypeptide ASRPS inhibits triple-negative breast cancer angiogenesis. J. Exp. Med. 2020, 217, jem.20190950. [Google Scholar] [CrossRef]
  85. Zhou, H.; Lou, F.; Bai, J.; Sun, Y.; Cai, W.; Sun, L.; Xu, Z.; Liu, Z.; Zhang, L.; Yin, Q.; et al. A peptide encoded by pri-miRNA-31 represses autoimmunity by promoting T(reg) differentiation. EMBO Rep. 2022, 23, e53475. [Google Scholar] [CrossRef]
  86. Li, X.; Zhou, H.; Lu, P.; Fang, Z.; Shi, G.; Tong, X.; Chen, W.; Jiang, G.; Zhang, P.; Tian, J.; et al. miPEP31 alleviates Ang II-induced hypertension in mice by occupying Cebpα binding sites in the pri-miR-31 promoter. Cardiovasc. Diabetol. 2024, 23, 249. [Google Scholar] [CrossRef]
  87. Zhou, Y.; Yuan, Y.; Yao, X.; Wang, L.; Yao, L.; Tang, D.; Chen, F.; Li, J. miPEP31 alleviates sepsis development by regulating Chi3l1-dependent macrophage polarization. Biol. Direct 2024, 19, 117. [Google Scholar] [CrossRef]
  88. Sang, Y.; Liu, J.-Y.; Wang, F.-Y.; Luo, X.-Y.; Chen, Z.-Q.; Zhuang, S.-M.; Zhu, Y. Mitochondrial micropeptide STMP1 promotes G1/S transition by enhancing mitochondrial complex IV activity. Mol. Ther. 2022, 30, 2844–2855. [Google Scholar] [CrossRef]
  89. Xiang, X.; Fu, Y.; Zhao, K.; Miao, R.; Zhang, X.; Ma, X.; Liu, C.; Zhang, N.; Qu, K. Cellular senescence in hepatocellular carcinoma induced by a long non-coding RNA-encoded peptide PINT87aa by blocking FOXM1-mediated PHB2. Theranostics 2021, 11, 4929–4944. [Google Scholar] [CrossRef]
  90. Zhang, C.; Zhou, B.; Gu, F.; Liu, H.; Wu, H.; Yao, F.; Zheng, H.; Fu, H.; Chong, W.; Cai, S.; et al. Micropeptide PACMP inhibition elicits synthetic lethal effects by decreasing CtIP and poly(ADP-ribosyl)ation. Mol. Cell 2022, 82, 1297–1312.e8. [Google Scholar] [CrossRef]
  91. Peeters, M.K.R.; Baggerman, G.; Gabriels, R.; Pepermans, E.; Menschaert, G.; Boonen, K. Ion Mobility Coupled to a Time-of-Flight Mass Analyzer Combined With Fragment Intensity Predictions Improves Identification of Classical Bioactive Peptides and Small Open Reading Frame-Encoded Peptides. Front. Cell Dev. Biol. 2021, 9, 720570. [Google Scholar] [CrossRef]
  92. Periasamy, P.; Rajandran, S.; Ziegman, R.; Casey, M.; Nakamura, K.; Kore, H.; Datta, K.; Gowda, H. A simple organic solvent precipitation method to improve detection of low molecular weight proteins. Proteomics 2021, 21, e2100152. [Google Scholar] [CrossRef] [PubMed]
  93. Cassidy, L.; Helbig, A.O.; Kaulich, P.T.; Weidenbach, K.; Schmitz, R.A.; Tholey, A. Multidimensional separation schemes enhance the identification and molecular characterization of low molecular weight proteomes and short open reading frame-encoded peptides in top-down proteomics. J. Proteom. 2021, 230, 103988. [Google Scholar] [CrossRef] [PubMed]
  94. Valdivia-Francia, F.; Sendoel, A. No country for old methods: New tools for studying microproteins. iScience 2024, 27, 108972. [Google Scholar] [CrossRef] [PubMed]
  95. Brito Querido, J.; Díaz-López, I.; Ramakrishnan, V. The molecular basis of translation initiation and its regulation in eukaryotes. Nat. Rev. Mol. Cell Biol. 2024, 25, 168–186. [Google Scholar] [CrossRef]
  96. Kaulich, P.T.; Cassidy, L.; Bartel, J.; Schmitz, R.A.; Tholey, A. Multi-protease Approach for the Improved Identification and Molecular Characterization of Small Proteins and Short Open Reading Frame-Encoded Peptides. J. Proteome Res. 2021, 20, 2895–2903. [Google Scholar] [CrossRef]
  97. Cassidy, L.; Kaulich, P.T.; Tholey, A. Depletion of High-Molecular-Mass Proteins for the Identification of Small Proteins and Short Open Reading Frame Encoded Peptides in Cellular Proteomes. J. Proteome Res. 2019, 18, 1725–1734. [Google Scholar] [CrossRef]
  98. Peeters, M.K.R.; Menschaert, G. The hunt for sORFs: A multidisciplinary strategy. Exp. Cell Res. 2020, 391, 111923. [Google Scholar] [CrossRef]
  99. Yang, H.; Li, Q.; Stroup, E.K.; Wang, S.; Ji, Z. Widespread stable noncanonical peptides identified by integrated analyses of ribosome profiling and ORF features. Nat. Commun. 2024, 15, 1932. [Google Scholar] [CrossRef]
  100. Li, Y.; Zhou, H.; Chen, X.; Zheng, Y.; Kang, Q.; Hao, D.; Zhang, L.; Song, T.; Luo, H.; Hao, Y.; et al. SmProt: A Reliable Repository with Comprehensive Annotation of Small Proteins Identified from Ribosome Profiling. Genom. Proteom. Bioinform. 2021, 19, 602–610. [Google Scholar] [CrossRef]
  101. Leblanc, S.; Yala, F.; Provencher, N.; Lucier, J.-F.; Levesque, M.; Lapointe, X.; Jacques, J.-F.; Fournier, I.; Salzet, M.; Ouangraoua, A.; et al. OpenProt 2.0 builds a path to the functional characterization of alternative proteins. Nucleic Acids Res. 2024, 52, D522–D528. [Google Scholar] [CrossRef]
  102. Machkovech, H.M.; Bloom, J.D.; Subramaniam, A.R. Comprehensive profiling of translation initiation in influenza virus infected cells. PLoS Pathog. 2019, 15, e1007518. [Google Scholar] [CrossRef]
Figure 1. Biogenesis of miPEPs. The biogenesis of miPEPs begins with the transcription of genomic regions containing sORFs. These genomic regions include intergenic regions; pseudogenes; DNA sequences encoding the 5′ and 3′ UTRs and the CDS of mRNAs; mitochondrial DNA; as well as viral genome. Following transcription, the translation of sORFs into miPEPs can be mediated by ribosome recruitment via IRES, with further translation efficiency enhanced by m6A modifications. Additionally, miPEPs are also derived from functional sORFs present in various RNA molecules, including lncRNAs, circRNAs, pre-microRNAs, and lincRNAs.
Figure 1. Biogenesis of miPEPs. The biogenesis of miPEPs begins with the transcription of genomic regions containing sORFs. These genomic regions include intergenic regions; pseudogenes; DNA sequences encoding the 5′ and 3′ UTRs and the CDS of mRNAs; mitochondrial DNA; as well as viral genome. Following transcription, the translation of sORFs into miPEPs can be mediated by ribosome recruitment via IRES, with further translation efficiency enhanced by m6A modifications. Additionally, miPEPs are also derived from functional sORFs present in various RNA molecules, including lncRNAs, circRNAs, pre-microRNAs, and lincRNAs.
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Figure 2. Proposed mechanism of action of some representative miPEPs (MAVI1, PESP, and Stmp1) in virus–host interactions. MAVI1, encoded by LINC00998, targets MAVS on the mitochondria. By suppressing MAVS-mediated antiviral innate immune responses, MAVI1 facilitates VSV replication. PESP, encoded by lncRNA PCBP1-AS1, is stabilized by interacting with HSP90AA1. This stabilization promotes the transcription of ATG7, key regulator of autophagy, and contributes to elongation and maturation of autophagy, resulting in enhanced IAV replication. Stmp1, encoded by lncRNA 1810058I24Rik, is localized to the inner membrane of mitochondria. It promotes NLRP3 inflammasome activation by triggering reactive oxygen species (ROS) generation and inducing Ca2+ flux, potentially playing a role in virus–host interactions.
Figure 2. Proposed mechanism of action of some representative miPEPs (MAVI1, PESP, and Stmp1) in virus–host interactions. MAVI1, encoded by LINC00998, targets MAVS on the mitochondria. By suppressing MAVS-mediated antiviral innate immune responses, MAVI1 facilitates VSV replication. PESP, encoded by lncRNA PCBP1-AS1, is stabilized by interacting with HSP90AA1. This stabilization promotes the transcription of ATG7, key regulator of autophagy, and contributes to elongation and maturation of autophagy, resulting in enhanced IAV replication. Stmp1, encoded by lncRNA 1810058I24Rik, is localized to the inner membrane of mitochondria. It promotes NLRP3 inflammasome activation by triggering reactive oxygen species (ROS) generation and inducing Ca2+ flux, potentially playing a role in virus–host interactions.
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Sun, H.; Gu, R.; Tang, T.; Rai, K.R.; Chen, J.-L. Current Perspectives on Functional Involvement of Micropeptides in Virus–Host Interactions. Int. J. Mol. Sci. 2025, 26, 3651. https://doi.org/10.3390/ijms26083651

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Sun H, Gu R, Tang T, Rai KR, Chen J-L. Current Perspectives on Functional Involvement of Micropeptides in Virus–Host Interactions. International Journal of Molecular Sciences. 2025; 26(8):3651. https://doi.org/10.3390/ijms26083651

Chicago/Turabian Style

Sun, Haowen, Rongrong Gu, Tingting Tang, Kul Raj Rai, and Ji-Long Chen. 2025. "Current Perspectives on Functional Involvement of Micropeptides in Virus–Host Interactions" International Journal of Molecular Sciences 26, no. 8: 3651. https://doi.org/10.3390/ijms26083651

APA Style

Sun, H., Gu, R., Tang, T., Rai, K. R., & Chen, J.-L. (2025). Current Perspectives on Functional Involvement of Micropeptides in Virus–Host Interactions. International Journal of Molecular Sciences, 26(8), 3651. https://doi.org/10.3390/ijms26083651

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