The role of the ubiquitin–proteasome system in ER quality control

2005 ◽  
Vol 41 ◽  
pp. 99-112 ◽  
Author(s):  
Yihong Ye
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Mhc Class I ◽  
Heavy Chain ◽  
Ubiquitin Proteasome System ◽  
Cellular Proteins ◽  
Physiological Adaptation ◽  
Er Quality Control ◽  
Ubiquitin Proteasome

Misfolded endoplasmic reticulum (ER) proteins are eliminated by the retrotranslocation pathway in eukaryotes, which is an important physiological adaptation to ER stress. This pathway can be hijacked by certain viruses to destroy folded cellular proteins, such as MHC class I heavy chain. Recent studies have highlighted the importance of the ubiquitin–proteasome system (UPS) in this process.

scholarly journals TTC3-Mediated Protein Quality Control, A Potential Mechanism for Cognitive Impairment

2021 ◽  
Author(s):  
Xu Zhou ◽  
Xiongjin Chen ◽  
Tingting Hong ◽  
Miaoping Zhang ◽  
Yujie Cai ◽  
...  
Keyword(s):  
Quality Control ◽  
Cognitive Impairment ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Ubiquitin Proteasome System ◽  
Research Progress ◽  
Repeat Domain ◽  
Ubiquitin Proteasome ◽  
Domain 3

AbstractThe tetrapeptide repeat domain 3 (TTC3) gene falls within Down's syndrome (DS) critical region. Cognitive impairment is a common phenotype of DS and Alzheimer’s disease (AD), and overexpression of TTC3 can accelerate cognitive decline, but the specific mechanism is unknown. The TTC3-mediated protein quality control (PQC) mechanism, similar to the PQC system, is divided into three parts: it acts as a cochaperone to assist proteins in folding correctly; it acts as an E3 ubiquitin ligase (E3s) involved in protein degradation processes through the ubiquitin–proteasome system (UPS); and it may also eventually cause autophagy by affecting mitochondrial function. Thus, this article reviews the research progress on the structure, function, and metabolism of TTC3, including the recent research progress on TTC3 in DS and AD; the role of TTC3 in cognitive impairment through PQC in combination with the abovementioned attributes of TTC3; and the potential targets of TTC3 in the treatment of such diseases.

Protein Quality Control in Neurodegeneration and Neuroprotection

2020 ◽  
pp. 1-24
Author(s):  
Yasmeena Akhter ◽  
Jahangir Nabi ◽  
Hinna Hamid ◽  
Nahida Tabassum ◽  
Faheem Hyder Pottoo ◽  
...  
Keyword(s):  
Quality Control ◽  
Neurodegenerative Disorders ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Ubiquitin Proteasome System ◽  
Security System ◽  
Conformational Disorders ◽  
Ubiquitin Proteasome ◽  
Multi Level

Proteostasis is essential for regulating the integrity of the proteome. Disruption of proteostasis under some rigorous conditions leads to the aggregation and accumulation of misfolded toxic proteins, which plays a central role in the pathogenesis of protein conformational disorders. The protein quality control (PQC) system serves as a multi-level security system to shield cells from abnormal proteins. The intrinsic PQC systems maintaining proteostasis include the ubiquitin-proteasome system (UPS), chaperon-mediated autophagy (CMA), and autophagy-lysosome pathway (ALP) that serve to target misfolded proteins for unfolding, refolding, or degradation. Alterations of PQC systems in neurons have been implicated in the pathogenesis of various neurodegenerative disorders. This chapter provides an overview of PQC pathways to set a framework for discussion of the role of PQC in neurodegenerative disorders. Additionally, various pharmacological approaches targeting PQC are summarized.

scholarly journals Effects of ubiquitin C-terminal hydrolase L1 deficiency on mouse ova

Reproduction ◽  
2012 ◽  
Vol 143 (3) ◽  
pp. 271-279 ◽  
Author(s):  
Sayaka Koyanagi ◽  
Hiroko Hamasaki ◽  
Satoshi Sekiguchi ◽  
Kenshiro Hara ◽  
Yoshiyuki Ishii ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Transmission Electron Microscopy ◽  
Endoplasmic Reticulum ◽  
Proteomic Analysis ◽  
Ubiquitin Proteasome System ◽  
Underlying Mechanism ◽  
Wild Type ◽  
Transmission Electron ◽  
Ubiquitin Proteasome

Maternal proteins are rapidly degraded by the ubiquitin–proteasome system during oocyte maturation in mice. Ubiquitin C-terminal hydrolase L1 (UCHL1) is highly and specifically expressed in mouse ova and is involved in the polyspermy block. However, the role of UCHL1 in the underlying mechanism of polyspermy block is poorly understood. To address this issue, we performed a comprehensive proteomic analysis to identify maternal proteins that were relevant to the role of UCHL1 in mouse ova using UCHL1-deficientgad. Furthermore, we assessed morphological features ingadmouse ova using transmission electron microscopy. NACHT, LRR, and PYD domain-containing (NALP) family proteins and endoplasmic reticulum (ER) chaperones were identified by proteomic analysis. We also found that the ‘maternal antigen that embryos require’ (NLRP5 (MATER)) protein level increased significantly ingadmouse ova compared with that in wild-type mice. In an ultrastructural study,gadmouse ova contained less ER in the cortex than in wild-type mice. These results provide new insights into the role of UCHL1 in the mechanism of polyspermy block in mouse ova.

Quality Control of Gastric Proton Pump in the Endoplasmic Reticulum by Ubiquitin/Proteasome System

2003 ◽  
Vol 986 (1) ◽  
pp. 655-657
Author(s):  
SHINJI ASANO ◽  
TOHRU KIMURA ◽  
HOKARA ISHIZUKA ◽  
MAGOTOSHI MORII ◽  
NORIAKI TAKEGUCHI
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Proton Pump ◽  
Ubiquitin Proteasome System ◽  
Ubiquitin Proteasome ◽  
Gastric Proton Pump

scholarly journals The Capture of a Disabled Proteasome Identifies Erg25 as a Substrate for Endoplasmic Reticulum Associated Degradation

2020 ◽  
Vol 19 (11) ◽  
pp. 1896-1909
Author(s):  
Teresa M. Buck ◽  
Xuemei Zeng ◽  
Pamela S. Cantrell ◽  
Richard T. Cattley ◽  
Zikri Hasanbasri ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Ubiquitin Proteasome System ◽  
Sterol Synthesis ◽  
High Confidence ◽  
Assembly Pathway ◽  
Affinity Isolation ◽  
Proteasome Subunits ◽  
Ubiquitin Proteasome ◽  
Erad Pathway

Studies in the yeast Saccharomyces cerevisiae have helped define mechanisms underlying the activity of the ubiquitin–proteasome system (UPS), uncover the proteasome assembly pathway, and link the UPS to the maintenance of cellular homeostasis. However, the spectrum of UPS substrates is incompletely defined, even though multiple techniques—including MS—have been used. Therefore, we developed a substrate trapping proteomics workflow to identify previously unknown UPS substrates. We first generated a yeast strain with an epitope tagged proteasome subunit to which a proteasome inhibitor could be applied. Parallel experiments utilized inhibitor insensitive strains or strains lacking the tagged subunit. After affinity isolation, enriched proteins were resolved, in-gel digested, and analyzed by high resolution liquid chromatography-tandem MS. A total of 149 proteasome partners were identified, including all 33 proteasome subunits. When we next compared data between inhibitor sensitive and resistant cells, 27 proteasome partners were significantly enriched. Among these proteins were known UPS substrates and proteins that escort ubiquitinated substrates to the proteasome. We also detected Erg25 as a high-confidence partner. Erg25 is a methyl oxidase that converts dimethylzymosterol to zymosterol, a precursor of the plasma membrane sterol, ergosterol. Because Erg25 is a resident of the endoplasmic reticulum (ER) and had not previously been directly characterized as a UPS substrate, we asked whether Erg25 is a target of the ER associated degradation (ERAD) pathway, which most commonly mediates proteasome-dependent destruction of aberrant proteins. As anticipated, Erg25 was ubiquitinated and associated with stalled proteasomes. Further, Erg25 degradation depended on ERAD-associated ubiquitin ligases and was regulated by sterol synthesis. These data expand the cohort of lipid biosynthetic enzymes targeted for ERAD, highlight the role of the UPS in maintaining ER function, and provide a novel tool to uncover other UPS substrates via manipulations of our engineered strain.

Quantity and Quality Control of Gastric Proton Pump in the Endoplasmic Reticulum by Ubiquitin/Proteasome System†

Biochemistry ◽  
2003 ◽  
Vol 42 (17) ◽  
pp. 4771-4779 ◽  
Author(s):  
Tohru Kimura ◽  
Hokara Ishizuka ◽  
Ayumi Yoshida ◽  
Magotoshi Morii ◽  
Noriaki Takeguchi ◽  
...  
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Proton Pump ◽  
Ubiquitin Proteasome System ◽  
Ubiquitin Proteasome ◽  
Gastric Proton Pump

scholarly journals USP13 antagonizes gp78 to maintain functionality of a chaperone in ER-associated degradation

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Yanfen Liu ◽  
Nia Soetandyo ◽  
Jin-gu Lee ◽  
Liping Liu ◽  
Yue Xu ◽  
...  
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Substrate Specificity ◽  
Ubiquitin Ligase ◽  
Proteolytic Processing ◽  
Misfolded Proteins ◽  
Physiological Adaptation ◽  
Er Quality Control ◽  
Proteotoxic Stress ◽  
Chaperone Complex

Physiological adaptation to proteotoxic stress in the endoplasmic reticulum (ER) requires retrotranslocation of misfolded proteins into the cytoplasm for ubiquitination and elimination by ER-associated degradation (ERAD). A surprising paradox emerging from recent studies is that ubiquitin ligases (E3s) and deubiquitinases (DUBs), enzymes with opposing activities, can both promote ERAD. Here we demonstrate that the ERAD E3 gp78 can ubiquitinate not only ERAD substrates, but also the machinery protein Ubl4A, a key component of the Bag6 chaperone complex. Remarkably, instead of targeting Ubl4A for degradation, polyubiquitination is associated with irreversible proteolytic processing and inactivation of Bag6. Importantly, we identify USP13 as a gp78-associated DUB that eliminates ubiquitin conjugates from Ubl4A to maintain the functionality of Bag6. Our study reveals an unexpected paradigm in which a DUB prevents undesired ubiquitination to sharpen substrate specificity for an associated ubiquitin ligase partner and to promote ER quality control.

scholarly journals Ste6p Mutants Defective in Exit from the Endoplasmic Reticulum (ER) Reveal Aspects of an ER Quality Control Pathway inSaccharomyces cerevisiae

1998 ◽  
Vol 9 (10) ◽  
pp. 2767-2784 ◽  
Author(s):  
Diego Loayza ◽  
Amy Tam ◽  
Walter K. Schmidt ◽  
Susan Michaelis
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Subcellular Fractionation ◽  
Metabolic Labeling ◽  
Wild Type ◽  
Er Quality Control ◽  
Ubiquitin Proteasome ◽  
Mutant Forms ◽  
Er Membrane

We are studying the intracellular trafficking of the multispanning membrane protein Ste6p, the a-factor transporter inSaccharomyces cerevisiae and a member of the ATP-binding cassette superfamily of proteins. In the present study, we have used Ste6p as model for studying the process of endoplasmic reticulum (ER) quality control, about which relatively little is known in yeast. We have identified three mutant forms of Ste6p that are aberrantly ER retained, as determined by immunofluorescence and subcellular fractionation. By pulse-chase metabolic labeling, we demonstrate that these mutants define two distinct classes. The single member of Class I, Ste6–166p, is highly unstable. We show that its degradation involves the ubiquitin–proteasome system, as indicated by its in vivo stabilization in certain ubiquitin–proteasome mutants or when cells are treated with the proteasome inhibitor drug MG132. The two Class II mutant proteins, Ste6–13p and Ste6–90p, are hyperstable relative to wild-type Ste6p and accumulate in the ER membrane. This represents the first report of a single protein in yeast for which distinct mutant forms can be channeled to different outcomes by the ER quality control system. We propose that these two classes of ER-retained Ste6p mutants may define distinct checkpoint steps in a linear pathway of ER quality control in yeast. In addition, a screen for high-copy suppressors of the mating defect of one of the ER-retained ste6 mutants has identified a proteasome subunit, Hrd2p/p97, previously implicated in the regulated degradation of wild-type hydroxymethylglutaryl-CoA reductase in the ER membrane.

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