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Proteostasis and Proteasome Inhibitors

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 May 2019) | Viewed by 35315

Special Issue Editor

Special Issue Information

Dear Colleagues,

The function of proteins is largely affected by their tridimensional structure, nevertheless incorrect folding of proteins is an inevitable problem that is present in all eukaryotic organelles. Misfolded proteins often present reduced or even absent activity and can be the basis of several proteinopathies, including neurodegenerative diseases or even lysosomal storage disease. To prevent the aggregation of misfolded proteins, eukaryotic cells have evolved robust pathways that are often interconnected with compartmental protein quality control. These pathways detect misfolded proteins and action refolding into functional proteins using chaperones, sequestering them in large inclusions pathway proteins, small heat shock chaperone, or degrading them through the ubiquitin-proteasome system or autophagy. This special issue will be dedicated to all aspects of proteostasis, protein quality control pathways, and proteasome inhibitors.

Prof. Dr. David Pereira
Guest Editor

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Keywords

  • Proteostasis
  • Proteasome inhibitors
  • Proteotoxicity
  • Folding
  • Cancer
  • Lisosome storage diseases
  • Neurodegenerative diseases

Published Papers (6 papers)

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Research

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14 pages, 2493 KiB  
Article
Partial Failure of Proteostasis Systems Counteracting TDP-43 Aggregates in Neurodegenerative Diseases
by Roberta Cascella, Giulia Fani, Alessandra Bigi, Fabrizio Chiti and Cristina Cecchi
Int. J. Mol. Sci. 2019, 20(15), 3685; https://doi.org/10.3390/ijms20153685 - 27 Jul 2019
Cited by 18 | Viewed by 4294
Abstract
Frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are progressive and fatal neurodegenerative disorders showing mislocalization and cytosolic accumulation of TDP-43 inclusions in the central nervous system. The decrease in the efficiency of the clearance systems in aging, as well as the [...] Read more.
Frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are progressive and fatal neurodegenerative disorders showing mislocalization and cytosolic accumulation of TDP-43 inclusions in the central nervous system. The decrease in the efficiency of the clearance systems in aging, as well as the presence of genetic mutations of proteins associated with cellular proteostasis in the familial forms of TDP-43 proteinopathies, suggest that a failure of these protein degradation systems is a key factor in the aetiology of TDP-43 associated disorders. Here we show that the internalization of human pre-formed TDP-43 aggregates in the murine neuroblastoma N2a cells promptly resulted in their ubiquitination and hyperphosphorylation by endogenous machineries, mimicking the post-translational modifications observed in patients. Moreover, our data identify mitochondria as the main responsible sites for the alteration of calcium homeostasis induced by TDP-43 aggregates, which, in turn, stimulates an increase in reactive oxygen species and, finally, caspase activation. The inhibition of TDP-43 proteostasis in the presence of selective inhibitors against the proteasome and macroautophagy systems revealed that these two systems are both severely involved in TDP-43 accumulation and have a strong influence on each other in neurodegenerative disorders associated with TDP-43. Full article
(This article belongs to the Special Issue Proteostasis and Proteasome Inhibitors)
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Review

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25 pages, 3197 KiB  
Review
Cellular Responses to Proteasome Inhibition: Molecular Mechanisms and Beyond
by Nicolas Albornoz, Hianara Bustamante, Andrea Soza and Patricia Burgos
Int. J. Mol. Sci. 2019, 20(14), 3379; https://doi.org/10.3390/ijms20143379 - 10 Jul 2019
Cited by 38 | Viewed by 11810
Abstract
Proteasome inhibitors have been actively tested as potential anticancer drugs and in the treatment of inflammatory and autoimmune diseases. Unfortunately, cells adapt to survive in the presence of proteasome inhibitors activating a variety of cell responses that explain why these therapies have not [...] Read more.
Proteasome inhibitors have been actively tested as potential anticancer drugs and in the treatment of inflammatory and autoimmune diseases. Unfortunately, cells adapt to survive in the presence of proteasome inhibitors activating a variety of cell responses that explain why these therapies have not fulfilled their expected results. In addition, all proteasome inhibitors tested and approved by the FDA have caused a variety of side effects in humans. Here, we describe the different types of proteasome complexes found within cells and the variety of regulators proteins that can modulate their activities, including those that are upregulated in the context of inflammatory processes. We also summarize the adaptive cellular responses activated during proteasome inhibition with special emphasis on the activation of the Autophagic-Lysosomal Pathway (ALP), proteaphagy, p62/SQSTM1 enriched-inclusion bodies, and proteasome biogenesis dependent on Nrf1 and Nrf2 transcription factors. Moreover, we discuss the role of IRE1 and PERK sensors in ALP activation during ER stress and the involvement of two deubiquitinases, Rpn11 and USP14, in these processes. Finally, we discuss the aspects that should be currently considered in the development of novel strategies that use proteasome activity as a therapeutic target for the treatment of human diseases. Full article
(This article belongs to the Special Issue Proteostasis and Proteasome Inhibitors)
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19 pages, 759 KiB  
Review
Role of the Ubiquitin Proteasome System (UPS) in the HIV-1 Life Cycle
by Vivian K. Rojas and In-Woo Park
Int. J. Mol. Sci. 2019, 20(12), 2984; https://doi.org/10.3390/ijms20122984 - 19 Jun 2019
Cited by 11 | Viewed by 4032
Abstract
Given that the ubiquitin proteasome system (UPS) is the major protein degradation process in the regulation of a wide variety of cellular processes in eukaryotic cells, including alteration of cellular location, modulation of protein activity, and regulation of protein interaction, it is reasonable [...] Read more.
Given that the ubiquitin proteasome system (UPS) is the major protein degradation process in the regulation of a wide variety of cellular processes in eukaryotic cells, including alteration of cellular location, modulation of protein activity, and regulation of protein interaction, it is reasonable to suggest that the infecting HIV-1 and the invaded hosts exploit the UPS in a contest for survival and proliferation. However, to date, regulation of the HIV-1 life cycle has been mainly explained by the stage-specific expression of HIV-1 viral genes, not by elimination processes of the synthesized proteins after completion of their duties in the infected cells, which is also quintessential for understanding the molecular processes of the virus life cycle and thereby HIV-1 pathogenesis. In fact, several previous publications have indicated that the UPS plays a critical role in the regulation of the proteasomal degradation of viral and cellular counterparts at every step of the HIV-1 life cycle, from the virus entry to release of the assembled virus particles, which is integral for the regulation of survival and proliferation of the infecting HIV-1 and to replication restriction of the invading virus in the host. However, it is unknown whether and how these individual events taking place at different stages of the HIV-1 life cycle are orchestrated as an overall strategy to overcome the restrictions conferred by the host cells. Thus, in this review, we overview the interplay between HIV-1 viral and cellular proteins for restrictions/competitions for proliferation of the virus in the infected cell, which could open a new avenue for the development of therapeutics against HIV-1 via targeting a specific step of the proteasome degradation pathway during the HIV-1 life cycle. Full article
(This article belongs to the Special Issue Proteostasis and Proteasome Inhibitors)
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20 pages, 3018 KiB  
Review
Control Mechanisms of the Tumor Suppressor PDCD4: Expression and Functions
by Sachiko Matsuhashi, M. Manirujjaman, Hiroshi Hamajima and Iwata Ozaki
Int. J. Mol. Sci. 2019, 20(9), 2304; https://doi.org/10.3390/ijms20092304 - 09 May 2019
Cited by 84 | Viewed by 6715
Abstract
PDCD4 is a novel tumor suppressor to show multi-functions inhibiting cell growth, tumor invasion, metastasis, and inducing apoptosis. PDCD4 protein binds to the translation initiation factor eIF4A, some transcription factors, and many other factors and modulates the function of the binding partners. PDCD4 [...] Read more.
PDCD4 is a novel tumor suppressor to show multi-functions inhibiting cell growth, tumor invasion, metastasis, and inducing apoptosis. PDCD4 protein binds to the translation initiation factor eIF4A, some transcription factors, and many other factors and modulates the function of the binding partners. PDCD4 downregulation stimulates and PDCD4 upregulation inhibits the TPA-induced transformation of cells. However, PDCD4 gene mutations have not been found in tumor cells but gene expression was post transcriptionally downregulated by micro environmental factors such as growth factors and interleukins. In this review, we focus on the suppression mechanisms of PDCD4 protein that is induced by the tumor promotors EGF and TPA, and in the inflammatory conditions. PDCD4-protein is phosphorylated at 2 serines in the SCFβTRCP ubiquitin ligase binding sequences via EGF and/or TPA induced signaling pathway, ubiquitinated, by the ubiquitin ligase and degraded in the proteasome system. The PDCD4 protein synthesis is inhibited by microRNAs including miR21. Full article
(This article belongs to the Special Issue Proteostasis and Proteasome Inhibitors)
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21 pages, 1540 KiB  
Review
Non-Proteasomal UbL-UbA Family of Proteins in Neurodegeneration
by Salinee Jantrapirom, Luca Lo Piccolo and Masamitsu Yamaguchi
Int. J. Mol. Sci. 2019, 20(8), 1893; https://doi.org/10.3390/ijms20081893 - 17 Apr 2019
Cited by 7 | Viewed by 4312
Abstract
Ubiquitin-like/ubiquitin-associated proteins (UbL-UbA) are a well-studied family of non-proteasomal ubiquitin receptors that are evolutionarily conserved across species. Members of this non-homogenous family facilitate and support proteasomal activity by promoting different effects on proteostasis but exhibit diverse extra-proteasomal activities. Dysfunctional UbL-UbA proteins render cells, [...] Read more.
Ubiquitin-like/ubiquitin-associated proteins (UbL-UbA) are a well-studied family of non-proteasomal ubiquitin receptors that are evolutionarily conserved across species. Members of this non-homogenous family facilitate and support proteasomal activity by promoting different effects on proteostasis but exhibit diverse extra-proteasomal activities. Dysfunctional UbL-UbA proteins render cells, particularly neurons, more susceptible to stressors or aging and may cause earlier neurodegeneration. In this review, we summarized the properties and functions of UbL-UbA family members identified to date, with an emphasis on new findings obtained using Drosophila models showing a direct or indirect role in some neurodegenerative diseases. Full article
(This article belongs to the Special Issue Proteostasis and Proteasome Inhibitors)
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18 pages, 3278 KiB  
Review
Proteasome-Rich PaCS as an Oncofetal UPS Structure Handling Cytosolic Polyubiquitinated Proteins. In Vivo Occurrence, in Vitro Induction, and Biological Role
by Enrico Solcia, Vittorio Necchi, Patrizia Sommi and Vittorio Ricci
Int. J. Mol. Sci. 2018, 19(9), 2767; https://doi.org/10.3390/ijms19092767 - 14 Sep 2018
Cited by 1 | Viewed by 3503
Abstract
In this article, we outline and discuss available information on the cellular site and mechanism of proteasome interaction with cytosolic polyubiquitinated proteins and heat-shock molecules. The particulate cytoplasmic structure (PaCS) formed by barrel-like particles, closely reproducing in vivo the high-resolution structure of 26S [...] Read more.
In this article, we outline and discuss available information on the cellular site and mechanism of proteasome interaction with cytosolic polyubiquitinated proteins and heat-shock molecules. The particulate cytoplasmic structure (PaCS) formed by barrel-like particles, closely reproducing in vivo the high-resolution structure of 26S proteasome as isolated in vitro, has been detected in a variety of fetal and neoplastic cells, from living tissue or cultured cell lines. Specific trophic factors and interleukins were found to induce PaCS during in vitro differentiation of dendritic, natural killer (NK), or megakaryoblastic cells, apparently through activation of the MAPK-ERK pathway. Direct interaction of CagA bacterial oncoprotein with proteasome was shown inside the PaCSs of a Helicobacter pylori-infected gastric epithelium, a finding suggesting a role for PaCS in CagA-mediated gastric carcinogenesis. PaCS dissolution and autophagy were seen after withdrawal of inducing factors. PaCS-filled cell blebs and ectosomes were found in some cells and may represent a potential intercellular discharge and transport system of polyubiquitinated antigenic proteins. PaCS differs substantially from the inclusion bodies, sequestosomes, and aggresomes reported in proteinopathies like Huntington or Parkinson diseases, which usually lack PaCS. The latter seems more linked to conditions of increased cell proliferation/differentiation, implying an increased functional demand to the ubiquitin–proteasome system. Full article
(This article belongs to the Special Issue Proteostasis and Proteasome Inhibitors)
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