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ERAD and Ubiquitination
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ERAD and Ubiquitination

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 (18 December 2020) | Viewed by 36127

Special Issue Editors

Prof. Dr. Jun Imai

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Guest Editor
Laboratory of Physiological Chemistry, Faculty of Pharmacy, Department of Pharmacy, Takasaki University of Health and Welfare, 60 Nakaorui-machi, Takasaki-shi, Gunmma 370-0033, Japan
Interests: cross presentation; dendritic cell; the ubiquitin proteasome system; antigen presentation
Special Issues, Collections and Topics in MDPI journals
Dr. Nobuko Hosokawa

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Guest Editor
Laboratory of Molecular and Cellular Biology, Institute for Frontier Life and Medical Sciences, Kyoto University, 53 Kawahara-cho, Sakyo-ku, Kyoto City, Kyoto 606-8507, Japan
Interests: molecular chaperones; ERAD; ER quality control; protein aggregation; intracellular transport; collagens; glycoproteins; N-glycans; lectins

Special Issue Information

Dear Colleagues,

ERAD (Endoplasmic Reticulum-Associated Degradation) has been identified as a cellular pathway of the protein quality control system in ER, in which specifically recognized misfolded proteins or unassembled proteins in ER were retro-transported out of ER lumen into the cytosol, ubiquitinated, and degraded by proteasomes. The ubiquitination in ERAD plays a central role in the degradation of ERAD-substrates by proteasomes but also in a recognition signal of retro-translocation and adjustments signals among ERAD-related molecular machinery. The disorders of ERAD-related ubiquitinations are the results of activation of UPR (unfolded protein response), and recent investigations revealed that UPR plays substantial roles in tumor progression, immunity, and aging. In this Special Issue of IJMS, we shall address the role of the ubiquitinations in ERAD. These analyses would show the expanding roles of ERAD-related ubiquitination other than in cellular homeostasis.

Dr. Jun Imai
Dr. Nobuko Hosokawa
Guest Editors

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Published Papers (6 papers)

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Research

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16 pages, 4602 KiB  
Article
Derlin-3 Is Required for Changes in ERAD Complex Formation under ER Stress
by Yuka Eura, Toshiyuki Miyata and Koichi Kokame
Int. J. Mol. Sci. 2020, 21(17), 6146; https://doi.org/10.3390/ijms21176146 - 26 Aug 2020
Cited by 18 | Viewed by 3891
Abstract
Endoplasmic reticulum (ER)-associated protein degradation (ERAD) is a quality control system that induces the degradation of ER terminally misfolded proteins. The ERAD system consists of complexes of multiple ER membrane-associated and luminal proteins that function cooperatively. We aimed to reveal the role of [...] Read more.
Endoplasmic reticulum (ER)-associated protein degradation (ERAD) is a quality control system that induces the degradation of ER terminally misfolded proteins. The ERAD system consists of complexes of multiple ER membrane-associated and luminal proteins that function cooperatively. We aimed to reveal the role of Derlin-3 in the ERAD system using the liver, pancreas, and kidney obtained from different mouse genotypes. We performed coimmunoprecipitation and sucrose density gradient centrifugation to unravel the dynamic nature of ERAD complexes. We observed that Derlin-3 is exclusively expressed in the pancreas, and its deficiency leads to the destabilization of Herp and accumulation of ERAD substrates. Under normal conditions, Complex-1a predominantly contains Herp, Derlin-2, HRD1, and SEL1L, and under ER stress, Complex-1b contains Herp, Derlin-3 (instead of Derlin-2), HRD1, and SEL1L. Complex-2 is upregulated under ER stress and contains Derlin-1, Derlin-2, p97, and VIMP. Derlin-3 deficiency suppresses the transition of Derlin-2 from Complex-1a to Complex-2 under ER stress. In the pancreas, Derlin-3 deficiency blocks Derlin-2 transition. In conclusion, the composition of ERAD complexes is tissue-specific and changes in response to ER stress in a Derlin-3-dependent manner. Derlin-3 may play a key role in changing ERAD complex compositions to overcome ER stress. Full article
(This article belongs to the Special Issue ERAD and Ubiquitination)
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19 pages, 3274 KiB  
Article
Endoplasmic Reticulum Associated Degradation of Spinocerebellar Ataxia-Related CD10 Cysteine Mutant
by Mai Kanuka, Fuka Ouchi, Nagisa Kato, Riko Katsuki, Saori Ito, Kohta Miura, Masaki Hikida and Taku Tamura
Int. J. Mol. Sci. 2020, 21(12), 4237; https://doi.org/10.3390/ijms21124237 - 14 Jun 2020
Cited by 3 | Viewed by 2813
Abstract
Spinocerebellar ataxia (SCA) is one of the most severe neurodegenerative diseases and is often associated with misfolded protein aggregates derived from the genetic mutation of related genes. Recently, mutations in CD10 such as C143Y have been identified as SCA type 43. CD10, also [...] Read more.
Spinocerebellar ataxia (SCA) is one of the most severe neurodegenerative diseases and is often associated with misfolded protein aggregates derived from the genetic mutation of related genes. Recently, mutations in CD10 such as C143Y have been identified as SCA type 43. CD10, also known as neprilysin or neuroendopeptidase, digests functional neuropeptides, such as amyloid beta, in the extracellular region. In this study, we explored the cellular behavior of CD10 C143Y to gain an insight into the functional relationship of the mutation and SCA pathology. We found that wild-type CD10 is expressed on the plasma membrane and exhibits endopeptidase activity in a cultured cell line. CD10 C143Y, however, forms a disulfide bond-mediated oligomer that does not appear by the wild-type CD10. Furthermore, the CD10 C143Y mutant was retained in the endoplasmic reticulum (ER) by the molecular chaperone BiP and was degraded through the ER-associated degradation (ERAD) process, in which representative ERAD factors including EDEM1, SEL1L, and Hrd1 participate in the degradation. Suppression of CD10 C143Y ERAD recovers intracellular transport but not enzymatic activity. Our results indicate that the C143Y mutation in CD10 negatively affects protein maturation and results in ER retention and following ERAD. These findings provide beneficial insight into SCA type 43 pathology. Full article
(This article belongs to the Special Issue ERAD and Ubiquitination)
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Review

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14 pages, 1398 KiB  
Review
Potential Physiological Relevance of ERAD to the Biosynthesis of GPI-Anchored Proteins in Yeast
by Kunio Nakatsukasa
Int. J. Mol. Sci. 2021, 22(3), 1061; https://doi.org/10.3390/ijms22031061 - 21 Jan 2021
Cited by 6 | Viewed by 5623
Abstract
Misfolded and/or unassembled secretory and membrane proteins in the endoplasmic reticulum (ER) may be retro-translocated into the cytoplasm, where they undergo ER-associated degradation, or ERAD. The mechanisms by which misfolded proteins are recognized and degraded through this pathway have been studied extensively; however, [...] Read more.
Misfolded and/or unassembled secretory and membrane proteins in the endoplasmic reticulum (ER) may be retro-translocated into the cytoplasm, where they undergo ER-associated degradation, or ERAD. The mechanisms by which misfolded proteins are recognized and degraded through this pathway have been studied extensively; however, our understanding of the physiological role of ERAD remains limited. This review describes the biosynthesis and quality control of glycosylphosphatidylinositol (GPI)-anchored proteins and briefly summarizes the relevance of ERAD to these processes. While recent studies suggest that ERAD functions as a fail-safe mechanism for the degradation of misfolded GPI-anchored proteins, several pieces of evidence suggest an intimate interaction between ERAD and the biosynthesis of GPI-anchored proteins. Full article
(This article belongs to the Special Issue ERAD and Ubiquitination)
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26 pages, 6651 KiB  
Review
Mitochondrial Surveillance by Cdc48/p97: MAD vs. Membrane Fusion
by Mafalda Escobar-Henriques and Vincent Anton
Int. J. Mol. Sci. 2020, 21(18), 6841; https://doi.org/10.3390/ijms21186841 - 18 Sep 2020
Cited by 17 | Viewed by 5081
Abstract
Cdc48/p97 is a ring-shaped, ATP-driven hexameric motor, essential for cellular viability. It specifically unfolds and extracts ubiquitylated proteins from membranes or protein complexes, mostly targeting them for proteolytic degradation by the proteasome. Cdc48/p97 is involved in a multitude of cellular processes, reaching from [...] Read more.
Cdc48/p97 is a ring-shaped, ATP-driven hexameric motor, essential for cellular viability. It specifically unfolds and extracts ubiquitylated proteins from membranes or protein complexes, mostly targeting them for proteolytic degradation by the proteasome. Cdc48/p97 is involved in a multitude of cellular processes, reaching from cell cycle regulation to signal transduction, also participating in growth or death decisions. The role of Cdc48/p97 in endoplasmic reticulum-associated degradation (ERAD), where it extracts proteins targeted for degradation from the ER membrane, has been extensively described. Here, we present the roles of Cdc48/p97 in mitochondrial regulation. We discuss mitochondrial quality control surveillance by Cdc48/p97 in mitochondrial-associated degradation (MAD), highlighting the potential pathologic significance thereof. Furthermore, we present the current knowledge of how Cdc48/p97 regulates mitofusin activity in outer membrane fusion and how this may impact on neurodegeneration. Full article
(This article belongs to the Special Issue ERAD and Ubiquitination)
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21 pages, 2962 KiB  
Review
Ubiquitination in the ERAD Process
by Anna Lopata, Andreas Kniss, Frank Löhr, Vladimir V. Rogov and Volker Dötsch
Int. J. Mol. Sci. 2020, 21(15), 5369; https://doi.org/10.3390/ijms21155369 - 28 Jul 2020
Cited by 42 | Viewed by 10018
Abstract
In this review, we focus on the ubiquitination process within the endoplasmic reticulum associated protein degradation (ERAD) pathway. Approximately one third of all synthesized proteins in a cell are channeled into the endoplasmic reticulum (ER) lumen or are incorporated into the ER membrane. [...] Read more.
In this review, we focus on the ubiquitination process within the endoplasmic reticulum associated protein degradation (ERAD) pathway. Approximately one third of all synthesized proteins in a cell are channeled into the endoplasmic reticulum (ER) lumen or are incorporated into the ER membrane. Since all newly synthesized proteins enter the ER in an unfolded manner, folding must occur within the ER lumen or co-translationally, rendering misfolding events a serious threat. To prevent the accumulation of misfolded protein in the ER, proteins that fail the quality control undergo retrotranslocation into the cytosol where they proceed with ubiquitination and degradation. The wide variety of misfolded targets requires on the one hand a promiscuity of the ubiquitination process and on the other hand a fast and highly processive mechanism. We present the various ERAD components involved in the ubiquitination process including the different E2 conjugating enzymes, E3 ligases, and E4 factors. The resulting K48-linked and K11-linked ubiquitin chains do not only represent a signal for degradation by the proteasome but are also recognized by the AAA+ ATPase Cdc48 and get in the process of retrotranslocation modified by enzymes bound to Cdc48. Lastly we discuss the conformations adopted in particular by K48-linked ubiquitin chains and their importance for degradation. Full article
(This article belongs to the Special Issue ERAD and Ubiquitination)
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23 pages, 1473 KiB  
Review
ER-Resident Transcription Factor Nrf1 Regulates Proteasome Expression and Beyond
by Jun Hamazaki and Shigeo Murata
Int. J. Mol. Sci. 2020, 21(10), 3683; https://doi.org/10.3390/ijms21103683 - 23 May 2020
Cited by 24 | Viewed by 8115
Abstract
Protein folding is a substantively error prone process, especially when it occurs in the endoplasmic reticulum (ER). The highly exquisite machinery in the ER controls secretory protein folding, recognizes aberrant folding states, and retrotranslocates permanently misfolded proteins from the ER back to the [...] Read more.
Protein folding is a substantively error prone process, especially when it occurs in the endoplasmic reticulum (ER). The highly exquisite machinery in the ER controls secretory protein folding, recognizes aberrant folding states, and retrotranslocates permanently misfolded proteins from the ER back to the cytosol; these misfolded proteins are then degraded by the ubiquitin–proteasome system termed as the ER-associated degradation (ERAD). The 26S proteasome is a multisubunit protease complex that recognizes and degrades ubiquitinated proteins in an ATP-dependent manner. The complex structure of the 26S proteasome requires exquisite regulation at the transcription, translation, and molecular assembly levels. Nuclear factor erythroid-derived 2-related factor 1 (Nrf1; NFE2L1), an ER-resident transcription factor, has recently been shown to be responsible for the coordinated expression of all the proteasome subunit genes upon proteasome impairment in mammalian cells. In this review, we summarize the current knowledge regarding the transcriptional regulation of the proteasome, as well as recent findings concerning the regulation of Nrf1 transcription activity in ER homeostasis and metabolic processes. Full article
(This article belongs to the Special Issue ERAD and Ubiquitination)
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