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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 September 2020) | Viewed by 65713

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Prof. Dr. Martin Holcik

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Guest Editor

Department of Health Sciences, Carleton University, Ottawa, ON K1S 5B6, Canada
Interests: mRNA translation; tRNA; mitochondrial disease; cell death; signaling
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The ability of cells to adapt to stress is crucial for their survival. The stress conditions that cells must respond to—such as hypoxia, inflammation, and drug exposure—often feature prominently in varied pathological states such as cancer, diabetes, and obesity. One of the key cellular adaptation strategies that have evolved to allow organisms to respond to such conditions includes the regulation of protein synthesis (mRNA translation), providing the rapid and reversible regulation of the cellular proteome. Closely regulated protein synthesis plays a central role in virtually all fundamental biological processes; conversely, dysregulated translation has been implicated in disease pathogenesis. Although protein synthesis has been studied for over eight decades, the basic mechanistic underpinnings of gene expression regulation at the translation level during pathological conditions are still not completely understood.

This Special Issue, “Protein Synthesis and Disease”, will cover a selection of recent research topics and current review articles specifically examining the role of dysregulated protein synthesis in disease.

Prof. Martin Holcik
Guest Editor

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Keywords

mRNA translation
Protein synthesis and cellular stress response
Protein synthesis and human disease
Ribosome
tRNA
Mitochondrial protein synthesis
Targeting translation for therapy

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Published Papers (11 papers)

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Research

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19 pages, 2767 KiB

Open AccessArticle

Lithium Chloride Sensitivity in Yeast and Regulation of Translation

by Maryam Hajikarimlou, Kathryn Hunt, Grace Kirby, Sarah Takallou, Sasi Kumar Jagadeesan, Katayoun Omidi, Mohsen Hooshyar, Daniel Burnside, Houman Moteshareie, Mohan Babu, Myron Smith, Martin Holcik, Bahram Samanfar and Ashkan Golshani

Int. J. Mol. Sci. 2020, 21(16), 5730; https://doi.org/10.3390/ijms21165730 - 10 Aug 2020

Cited by 13 | Viewed by 5574

Abstract

For decades, lithium chloride (LiCl) has been used as a treatment option for those living with bipolar disorder (BD). As a result, many studies have been conducted to examine its mode of action, toxicity, and downstream cellular responses. We know that LiCl is able to affect cell signaling and signaling transduction pathways through protein kinase C and glycogen synthase kinase-3, which are considered to be important in regulating gene expression at the translational level. However, additional downstream effects require further investigation, especially in translation pathway. In yeast, LiCl treatment affects the expression, and thus the activity, of PGM2, a phosphoglucomutase involved in sugar metabolism. Inhibition of PGM2 leads to the accumulation of intermediate metabolites of galactose metabolism causing cell toxicity. However, it is not fully understood how LiCl affects gene expression in this matter. In this study, we identified three genes, NAM7, PUS2, and RPL27B, which increase yeast LiCl sensitivity when deleted. We further demonstrate that NAM7, PUS2, and RPL27B influence translation and exert their activity through the 5′-Untranslated region (5′-UTR) of PGM2 mRNA in yeast. Full article

(This article belongs to the Special Issue Protein Synthesis and Disease)

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19 pages, 4331 KiB

Open AccessArticle

UL36 Encoded by Marek’s Disease Virus Exhibits Linkage-Specific Deubiquitinase Activity

by Junyan Lin, Yongxing Ai, Hongda Zhou, Yan Lv, Menghan Wang, Jiacui Xu, Cong Yu, Huanmin Zhang and Mengyun Wang

Int. J. Mol. Sci. 2020, 21(5), 1783; https://doi.org/10.3390/ijms21051783 - 5 Mar 2020

Cited by 6 | Viewed by 4038

Abstract

(1) Background: Deubiquitinase (DUB) regulates various important cellular processes via reversing the protein ubiquitination. The N-terminal fragment of a giant tegument protein, UL36, encoded by the Marek’s disease (MD) virus (MDV), encompasses a putative DUB (UL36-DUB) and shares no homology with any known DUBs. The N-terminus 75 kDa fragment of UL36 exists in MD T lymphoma cells at a high level and participates in MDV pathogenicity. (2) Methods: To characterize deubiquitinating activity and substrate specificity of UL36-DUB, the UL36 N-terminal fragments, UL36(323), UL36(480), and mutants were prepared using the Bac-to-Bac system. The deubiquitinating activity and substrate specificity of these recombinant UL36-DUBs were analyzed using various ubiquitin (Ub) or ubiquitin-like (UbL) substrates and activity-based deubiquitinating enzyme probes. (3) Results: The results indicated that wild type UL36-DUBs show a different hydrolysis ability against varied types of ubiquitin chains. These wild type UL36-DUBs presented the highest activity to K11, K48, and K63 linkage Ub chains, weak activity to K6, K29, and K33 Ub chains, and no activity to K27 linkage Ub chain. UL36 has higher cleavage efficiency for K48 and K63 poly-ubiquitin than linear ubiquitin chain (M1-Ub4), but no activity on various ubiquitin-like modifiers. The mutation of C98 and H234 residues eliminated the deubiquitinating activity of UL36-DUB. D232A mutation impacted, but did not eliminated UL36(480) activity. The Ub-Br probe can bind to wild type UL36-DUB and mutants UL36(480)^H234A and UL36(480)^D232A, but not C98 mutants. These in vitro results suggested that the C98 and H234 are essential catalytic residues of UL36-DUB. UL36-DUB exhibited a strict substrate specificity. Inhibition assay revealed that UL36-DUB exhibits resistance to the Roche protease inhibitor cocktail and serine protease inhibitor, but not to the Solarbio protease inhibitor cocktail. (4) Conclusions: UL36-DUB exhibited a strict substrate preference, and the protocol developed in the current study for obtaining active UL36-DUB protein should promote the high-throughput screening of UL36 inhibitors and the study on the function of MDV-encoded UL36. Full article

(This article belongs to the Special Issue Protein Synthesis and Disease)

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16 pages, 3501 KiB

Open AccessArticle

Repurposing Potential of Riluzole as an ITAF Inhibitor in mTOR Therapy Resistant Glioblastoma

by Angelica Benavides-Serrato, Jacquelyn T. Saunders, Brent Holmes, Robert N. Nishimura, Alan Lichtenstein and Joseph Gera

Int. J. Mol. Sci. 2020, 21(1), 344; https://doi.org/10.3390/ijms21010344 - 5 Jan 2020

Cited by 19 | Viewed by 4955

Abstract

Internal ribosome entry site (IRES)-mediated protein synthesis has been demonstrated to play an important role in resistance to mechanistic target of rapamycin (mTOR) targeted therapies. Previously, we have demonstrated that the IRES trans-acting factor (ITAF), hnRNP A1 is required to promote IRES activity and small molecule inhibitors which bind specifically to this ITAF and curtail IRES activity, leading to mTOR inhibitor sensitivity. Here we report the identification of riluzole (Rilutek^®), an FDA-approved drug for amyotrophic lateral sclerosis (ALS), via an in silico docking analysis of FDA-approved compounds, as an inhibitor of hnRNP A1. In a riluzole-bead coupled binding assay and in surface plasmon resonance imaging analyses, riluzole was found to directly bind to hnRNP A1 and inhibited IRES activity via effects on ITAF/RNA-binding. Riluzole also demonstrated synergistic anti-glioblastoma (GBM) affects with mTOR inhibitors in vitro and in GBM xenografts in mice. These data suggest that repurposing riluzole, used in conjunction with mTOR inhibitors, may serve as an effective therapeutic option in glioblastoma. Full article

(This article belongs to the Special Issue Protein Synthesis and Disease)

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Review

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21 pages, 1171 KiB

Open AccessReview

Ionizing Radiation and Translation Control: A Link to Radiation Hormesis?

by Usha Kabilan, Tyson E. Graber, Tommy Alain and Dmitry Klokov

Int. J. Mol. Sci. 2020, 21(18), 6650; https://doi.org/10.3390/ijms21186650 - 11 Sep 2020

Cited by 20 | Viewed by 5444

Abstract

Protein synthesis, or mRNA translation, is one of the most energy-consuming functions in cells. Translation of mRNA into proteins is thus highly regulated by and integrated with upstream and downstream signaling pathways, dependent on various transacting proteins and cis-acting elements within the substrate mRNAs. Under conditions of stress, such as exposure to ionizing radiation, regulatory mechanisms reprogram protein synthesis to translate mRNAs encoding proteins that ensure proper cellular responses. Interestingly, beneficial responses to low-dose radiation exposure, known as radiation hormesis, have been described in several models, but the molecular mechanisms behind this phenomenon are largely unknown. In this review, we explore how differences in cellular responses to high- vs. low-dose ionizing radiation are realized through the modulation of molecular pathways with a particular emphasis on the regulation of mRNA translation control. Full article

(This article belongs to the Special Issue Protein Synthesis and Disease)

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26 pages, 1575 KiB

Open AccessReview

Translation Regulation by eIF2α Phosphorylation and mTORC1 Signaling Pathways in Non-Communicable Diseases (NCDs)

by Tiffany J. Rios-Fuller, Melanie Mahe, Beth Walters, Dounia Abbadi, Sandra Pérez-Baos, Abhilash Gadi, John J. Andrews, Olga Katsara, C. Theresa Vincent and Robert J. Schneider

Int. J. Mol. Sci. 2020, 21(15), 5301; https://doi.org/10.3390/ijms21155301 - 26 Jul 2020

Cited by 30 | Viewed by 9259

Abstract

Non-communicable diseases (NCDs) are medical conditions that, by definition, are non-infectious and non-transmissible among people. Much of current NCDs are generally due to genetic, behavioral, and metabolic risk factors that often include excessive alcohol consumption, smoking, obesity, and untreated elevated blood pressure, and share many common signal transduction pathways. Alterations in cell and physiological signaling and transcriptional control pathways have been well studied in several human NCDs, but these same pathways also regulate expression and function of the protein synthetic machinery and mRNA translation which have been less well investigated. Alterations in expression of specific translation factors, and disruption of canonical mRNA translational regulation, both contribute to the pathology of many NCDs. The two most common pathological alterations that contribute to NCDs discussed in this review will be the regulation of eukaryotic initiation factor 2 (eIF2) by the integrated stress response (ISR) and the mammalian target of rapamycin complex 1 (mTORC1) pathways. Both pathways integrally connect mRNA translation activity to external and internal physiological stimuli. Here, we review the role of ISR control of eIF2 activity and mTORC1 control of cap-mediated mRNA translation in some common NCDs, including Alzheimer’s disease, Parkinson’s disease, stroke, diabetes mellitus, liver cirrhosis, chronic obstructive pulmonary disease (COPD), and cardiac diseases. Our goal is to provide insights that further the understanding as to the important role of translational regulation in the pathogenesis of these diseases. Full article

(This article belongs to the Special Issue Protein Synthesis and Disease)

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23 pages, 1688 KiB

Open AccessReview

General and Target-Specific DExD/H RNA Helicases in Eukaryotic Translation Initiation

by Leo Shen and Jerry Pelletier

Int. J. Mol. Sci. 2020, 21(12), 4402; https://doi.org/10.3390/ijms21124402 - 20 Jun 2020

Cited by 46 | Viewed by 7013

Abstract

DExD (DDX)- and DExH (DHX)-box RNA helicases, named after their Asp-Glu-x-Asp/His motifs, are integral to almost all RNA metabolic processes in eukaryotic cells. They play myriad roles in processes ranging from transcription and mRNA-protein complex remodeling, to RNA decay and translation. This last facet, translation, is an intricate process that involves DDX/DHX helicases and presents a regulatory node that is highly targetable. Studies aimed at better understanding this family of conserved proteins have revealed insights into their structures, catalytic mechanisms, and biological roles. They have also led to the development of chemical modulators that seek to exploit their essential roles in diseases. Herein, we review the most recent insights on several general and target-specific DDX/DHX helicases in eukaryotic translation initiation. Full article

(This article belongs to the Special Issue Protein Synthesis and Disease)

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16 pages, 925 KiB

Open AccessReview

Regulation of Epithelial-to-Mesenchymal Transition by Alternative Translation Initiation Mechanisms and Its Implications for Cancer Metastasis

by Amit Bera and Stephen M. Lewis

Int. J. Mol. Sci. 2020, 21(11), 4075; https://doi.org/10.3390/ijms21114075 - 7 Jun 2020

Cited by 17 | Viewed by 4619

Abstract

Translation initiation plays a critical role in the regulation of gene expression for development and disease conditions. During the processes of development and disease, cells select specific mRNAs to be translated by controlling the use of diverse translation initiation mechanisms. Cells often switch translation initiation from a cap-dependent to a cap-independent mechanism during epithelial-to-mesenchymal transition (EMT), a process that plays an important role in both development and disease. EMT is involved in tumor metastasis because it leads to cancer cell migration and invasion, and is also associated with chemoresistance. In this review we will provide an overview of both the internal ribosome entry site (IRES)-dependent and N⁶-methyladenosine (m⁶A)-mediated translation initiation mechanisms and discuss how cap-independent translation enables cells from primary epithelial tumors to achieve a motile mesenchymal-like phenotype, which in turn drives tumor metastasis. Full article

(This article belongs to the Special Issue Protein Synthesis and Disease)

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14 pages, 780 KiB

Open AccessReview

Emerging Roles of Gemin5: From snRNPs Assembly to Translation Control

by Encarnacion Martinez-Salas, Azman Embarc-Buh and Rosario Francisco-Velilla

Int. J. Mol. Sci. 2020, 21(11), 3868; https://doi.org/10.3390/ijms21113868 - 29 May 2020

Cited by 35 | Viewed by 4495

Abstract

RNA-binding proteins (RBPs) play a pivotal role in the lifespan of RNAs. The disfunction of RBPs is frequently the cause of cell disorders which are incompatible with life. Furthermore, the ordered assembly of RBPs and RNAs in ribonucleoprotein (RNP) particles determines the function of biological complexes, as illustrated by the survival of the motor neuron (SMN) complex. Defects in the SMN complex assembly causes spinal muscular atrophy (SMA), an infant invalidating disease. This multi-subunit chaperone controls the assembly of small nuclear ribonucleoproteins (snRNPs), which are the critical components of the splicing machinery. However, the functional and structural characterization of individual members of the SMN complex, such as SMN, Gemin3, and Gemin5, have accumulated evidence for the additional roles of these proteins, unveiling their participation in other RNA-mediated events. In particular, Gemin5 is a multidomain protein that comprises tryptophan-aspartic acid (WD) repeat motifs at the N-terminal region, a dimerization domain at the middle region, and a non-canonical RNA-binding domain at the C-terminal end of the protein. Beyond small nuclear RNA (snRNA) recognition, Gemin5 interacts with a selective group of mRNA targets in the cell environment and plays a key role in reprogramming translation depending on the RNA partner and the cellular conditions. Here, we review recent studies on the SMN complex, with emphasis on the individual components regarding their involvement in cellular processes critical for cell survival. Full article

(This article belongs to the Special Issue Protein Synthesis and Disease)

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14 pages, 1323 KiB

Open AccessReview

Diseases Associated with Defects in tRNA CCA Addition

by Angelo Slade, Ribal Kattini, Chloe Campbell and Martin Holcik

Int. J. Mol. Sci. 2020, 21(11), 3780; https://doi.org/10.3390/ijms21113780 - 27 May 2020

Cited by 23 | Viewed by 4154

Abstract

tRNA nucleotidyl transferase 1 (TRNT1) is an essential enzyme catalyzing the addition of terminal cytosine-cytosine-adenosine (CCA) trinucleotides to all mature tRNAs, which is necessary for aminoacylation. It was recently discovered that partial loss-of-function mutations in TRNT1 are associated with various, seemingly unrelated human diseases including sideroblastic anemia with B-cell immunodeficiency, periodic fevers and developmental delay (SIFD), retinitis pigmentosa with erythrocyte microcytosis, and progressive B-cell immunodeficiency. In addition, even within the same disease, the severity and range of the symptoms vary greatly, suggesting a broad, pleiotropic impact of imparting TRNT1 function on diverse cellular systems. Here, we describe the current state of knowledge of the TRNT1 function and the phenotypes associated with mutations in TRNT1. Full article

(This article belongs to the Special Issue Protein Synthesis and Disease)

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24 pages, 3352 KiB

Open AccessReview

Emerging Roles for 3′ UTRs in Neurons

by Bongmin Bae and Pedro Miura

Int. J. Mol. Sci. 2020, 21(10), 3413; https://doi.org/10.3390/ijms21103413 - 12 May 2020

Cited by 56 | Viewed by 8627

Abstract

The 3′ untranslated regions (3′ UTRs) of mRNAs serve as hubs for post-transcriptional control as the targets of microRNAs (miRNAs) and RNA-binding proteins (RBPs). Sequences in 3′ UTRs confer alterations in mRNA stability, direct mRNA localization to subcellular regions, and impart translational control. Thousands of mRNAs are localized to subcellular compartments in neurons—including axons, dendrites, and synapses—where they are thought to undergo local translation. Despite an established role for 3′ UTR sequences in imparting mRNA localization in neurons, the specific RNA sequences and structural features at play remain poorly understood. The nervous system selectively expresses longer 3′ UTR isoforms via alternative polyadenylation (APA). The regulation of APA in neurons and the neuronal functions of longer 3′ UTR mRNA isoforms are starting to be uncovered. Surprising roles for 3′ UTRs are emerging beyond the regulation of protein synthesis and include roles as RBP delivery scaffolds and regulators of alternative splicing. Evidence is also emerging that 3′ UTRs can be cleaved, leading to stable, isolated 3′ UTR fragments which are of unknown function. Mutations in 3′ UTRs are implicated in several neurological disorders—more studies are needed to uncover how these mutations impact gene regulation and what is their relationship to disease severity. Full article

(This article belongs to the Special Issue Protein Synthesis and Disease)

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33 pages, 3444 KiB

Open AccessReview

Deeping in the Role of the MAP-Kinases Interacting Kinases (MNKs) in Cancer

by Celia Pinto-Díez, Raquel Ferreras-Martín, Rebeca Carrión-Marchante, Víctor M. González and María Elena Martín

Int. J. Mol. Sci. 2020, 21(8), 2967; https://doi.org/10.3390/ijms21082967 - 23 Apr 2020

Cited by 33 | Viewed by 6266

Abstract

The mitogen-activated protein kinase (MAPK)-interacting kinases (MNKs) are involved in oncogenic transformation and can promote metastasis and tumor progression. In human cells, there are four MNKs isoforms (MNK1a/b and MNK2a/b), derived from two genes by alternative splicing. These kinases play an important role controlling the expression of specific proteins involved in cell cycle, cell survival and cell motility via eukaryotic initiation factor 4E (eIF4E) regulation, but also through other substrates such as heterogeneous nuclear ribonucleoprotein A1, polypyrimidine tract-binding protein-associated splicing factor and Sprouty 2. In this review, we provide an overview of the role of MNK in human cancers, describing the studies conducted to date to elucidate the mechanism involved in the action of MNKs, as well as the development of MNK inhibitors in different hematological cancers and solid tumors. Full article

(This article belongs to the Special Issue Protein Synthesis and Disease)

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