scholarly journals Quality Control of ER Membrane Proteins by the RNF185/Membralin Ubiquitin Ligase Complex

2020 ◽  
Vol 80 (2) ◽  
pp. 374-375
Author(s):  
Michael L. van de Weijer ◽  
Logesvaran Krshnan ◽  
Sabrina Liberatori ◽  
Elena Navarro Guerrero ◽  
Jacob Robson-Tull ◽  
...  
Keyword(s):  
Quality Control ◽  
Membrane Proteins ◽  
Ubiquitin Ligase ◽  
Ubiquitin Ligase Complex ◽  
Er Membrane

scholarly journals Quality Control of ER Membrane Proteins by the RNF185/Membralin Ubiquitin Ligase Complex

2020 ◽  
Vol 79 (5) ◽  
pp. 768-781.e7 ◽  
Author(s):  
Michael L. van de Weijer ◽  
Logesvaran Krshnan ◽  
Sabrina Liberatori ◽  
Elena Navarro Guerrero ◽  
Jacob Robson-Tull ◽  
...  
Keyword(s):  
Quality Control ◽  
Membrane Proteins ◽  
Ubiquitin Ligase ◽  
Ubiquitin Ligase Complex ◽  
Er Membrane

scholarly journals In Vivo Action of the HRD Ubiquitin Ligase Complex: Mechanisms of Endoplasmic Reticulum Quality Control and Sterol Regulation

2001 ◽  
Vol 21 (13) ◽  
pp. 4276-4291 ◽  
Author(s):  
Richard G. Gardner ◽  
Alexander G. Shearer ◽  
Randolph Y. Hampton
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Ubiquitin Ligase ◽  
Sequence Similarity ◽  
High Specificity ◽  
Specific Sequence ◽  
Ubiquitin Ligase Complex ◽  
Ubiquitin Conjugating Enzyme ◽  
Conjugating Enzyme

ABSTRACT Ubiquitination is used to target both normal proteins for specific regulated degradation and misfolded proteins for purposes of quality control destruction. Ubiquitin ligases, or E3 proteins, promote ubiquitination by effecting the specific transfer of ubiquitin from the correct ubiquitin-conjugating enzyme, or E2 protein, to the target substrate. Substrate specificity is usually determined by specific sequence determinants, or degrons, in the target substrate that are recognized by the ubiquitin ligase. In quality control, however, a potentially vast collection of proteins with characteristic hallmarks of misfolding or misassembly are targeted with high specificity despite the lack of any sequence similarity between substrates. In order to understand the mechanisms of quality control ubiquitination, we have focused our attention on the first characterized quality control ubiquitin ligase, the HRD complex, which is responsible for the endoplasmic reticulum (ER)-associated degradation (ERAD) of numerous ER-resident proteins. Using an in vivo cross-linking assay, we directly examined the association of the separate HRDcomplex components with various ERAD substrates. We have discovered that the HRD ubiquitin ligase complex associates with both ERAD substrates and stable proteins, but only mediates ubiquitin-conjugating enzyme association with ERAD substrates. Our studies with the sterol pathway-regulated ERAD substrate Hmg2p, an isozyme of the yeast cholesterol biosynthetic enzyme HMG-coenzyme A reductase (HMGR), indicated that the HRD complex discerns between a degradation-competent “misfolded” state and a stable, tightly folded state. Thus, it appears that the physiologically regulated, HRD-dependent degradation of HMGR is effected by a programmed structural transition from a stable protein to a quality control substrate.

scholarly journals A stalled retrotranslocation complex reveals physical linkage between substrate recognition and proteasomal degradation during ER-associated degradation

2013 ◽  
Vol 24 (11) ◽  
pp. 1765-1775 ◽  
Author(s):  
Kunio Nakatsukasa ◽  
Jeffrey L. Brodsky ◽  
Takumi Kamura
Keyword(s):  
Endoplasmic Reticulum ◽  
Membrane Proteins ◽  
Ubiquitin Ligase ◽  
Substrate Recognition ◽  
Proteasomal Degradation ◽  
26S Proteasome ◽  
Endoplasmic Reticulum Associated Degradation ◽  
Ubiquitin Ligase Complex ◽  
Physical Linkage ◽  
Tightly Coupled

During endoplasmic reticulum–associated degradation (ERAD), misfolded lumenal and membrane proteins in the ER are recognized by the transmembrane Hrd1 ubiquitin ligase complex and retrotranslocated to the cytosol for ubiquitination and degradation. Although substrates are believed to be delivered to the proteasome only after the ATPase Cdc48p/p97 acts, there is limited knowledge about how the Hrd1 complex coordinates with Cdc48p/p97 and the proteasome to orchestrate substrate recognition and degradation. Here we provide evidence that inactivation of Cdc48p/p97 stalls retrotranslocation and triggers formation of a complex that contains the 26S proteasome, Cdc48p/p97, ubiquitinated substrates, select components of the Hrd1 complex, and the lumenal recognition factor, Yos9p. We propose that the actions of Cdc48p/p97 and the proteasome are tightly coupled during ERAD. Our data also support a model in which the Hrd1 complex links substrate recognition and degradation on opposite sides of the ER membrane.

scholarly journals Quality control of nonstop membrane proteins at the ER membrane and in the cytosol

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Shunsuke Arakawa ◽  
Kaori Yunoki ◽  
Toshiaki Izawa ◽  
Yasushi Tamura ◽  
Shuh-ichi Nishikawa ◽  
...  
Keyword(s):  
Quality Control ◽  
Membrane Proteins ◽  
Er Membrane

scholarly journals Human XTP3-B Forms an Endoplasmic Reticulum Quality Control Scaffold with the HRD1-SEL1L Ubiquitin Ligase Complex and BiP

2008 ◽  
Vol 283 (30) ◽  
pp. 20914-20924 ◽  
Author(s):  
Nobuko Hosokawa ◽  
Ikuo Wada ◽  
Koji Nagasawa ◽  
Tatsuya Moriyama ◽  
Katsuya Okawa ◽  
...  
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Ubiquitin Ligase ◽  
Ubiquitin Ligase Complex ◽  
Endoplasmic Reticulum Quality Control

scholarly journals Membrane-anchored ubiquitin ligase complex is required for the turnover of lysosomal membrane proteins

2015 ◽  
Vol 211 (3) ◽  
pp. 639-652 ◽  
Author(s):  
Ming Li ◽  
Tatsuhiro Koshi ◽  
Scott D. Emr
Keyword(s):  
Membrane Proteins ◽  
Ubiquitin Ligase ◽  
Degradation Process ◽  
Degradation Pathway ◽  
Interacting Proteins ◽  
Vacuole Membrane ◽  
Ubiquitin Ligase Complex ◽  
Storage Organelle ◽  
Lysosomal Membrane Proteins ◽  
Nutrient Homeostasis

Cells must regulate the abundance and activity of numerous nutrient transporters in different organelle membranes to achieve nutrient homeostasis. As the recycling center and major storage organelle, lysosomes are essential for maintaining nutrient homeostasis. However, very little is known about mechanisms that govern the regulation of its membrane proteins. In this study, we demonstrated that changes of Zn2+ levels trigger the downregulation of vacuolar Zn2+ transporters. Low Zn2+ levels cause the degradation of the influx transporter Cot1, whereas high Zn2+ levels trigger the degradation of the efflux channel Zrt3. The degradation process depends on the vacuole membrane recycling and degradation pathway. Unexpectedly, we identified a RING domain–containing E3 ligase Tul1 and its interacting proteins in the Dsc complex that are important for the ubiquitination of Cot1 and partial ubiquitination of Zrt3. Our study demonstrated that the Dsc complex can function at the vacuole to regulate the composition and lifetime of vacuolar membrane proteins.

scholarly journals The ART-Rsp5 ubiquitin ligase network comprises a plasma membrane quality control system that protects yeast cells from proteotoxic stress

eLife ◽  
2013 ◽  
Vol 2 ◽  
Author(s):  
Yingying Zhao ◽  
Jason A MacGurn ◽  
Max Liu ◽  
Scott Emr
Keyword(s):  
Quality Control ◽  
Plasma Membrane ◽  
Control System ◽  
Membrane Proteins ◽  
Cell Surface ◽  
Ubiquitin Ligase ◽  
Integral Membrane Proteins ◽  
Quality Control System ◽  
Er Quality Control ◽  
Proteotoxic Stress

Secretory cargo that cannot fold properly in the ER are selectively targeted for removal by a well-studied ER-associated degradation pathway, or ERAD. In contrast, very little is known about post-ER quality control mechanisms for damaged or misfolded integral membrane proteins. Here we describe a quality control function of the Rsp5-ART ubiquitin ligase adaptor network that functions to protect plasma membrane (PM) integrity. Failure to mediate this protective response during heat stress leads to toxic accumulation of misfolded integral membrane proteins at the cell surface, which causes loss of PM integrity and cell death. Thus, the Rsp5-ART network comprises a PM quality control system that works together with sequential quality control pathways in the ER and Golgi to (i) target the degradation of proteins that have exceeded their functional lifetime due to damage and/or misfolding and (ii) limit the toxic accumulation of specific proteins at the cell surface during proteotoxic stress.

scholarly journals The derlin Dfm1 promotes retrotranslocation of folded protein domains from the endoplasmic reticulum

2020 ◽  
Author(s):  
Daniel Fonseca ◽  
Pedro Carvalho
Keyword(s):  
Endoplasmic Reticulum ◽  
Ubiquitin Ligase ◽  
Protein Domains ◽  
Membrane Extraction ◽  
Membrane Component ◽  
Binding Domains ◽  
Modifying Factors ◽  
Ubiquitin Ligase Complex ◽  
Substrate Processing ◽  
Er Membrane

AbstractEndoplasmic reticulum (ER) proteins are degraded by proteasomes in the cytosol through ER-associated degradation (ERAD). This process involves retrotranslocation of substrates across the ER membrane, their ubiquitination and subsequent membrane extraction by the Cdc48/Npl4/Ufd1 ATPase complex prior delivery to proteasomes for degradation. Recently a mechanism for the retrotranslocation of misfolded substrates by the Hrd1 ubiquitin ligase complex was described. However, how substrates with folded luminal domains are retrotranslocated remains unknown. Here, we identify Dfm1 as an essential membrane component for the retrotranslocation of proteins with folded luminal domains. Both Dfm1 intramembrane rhomboid-like and the cytosolic Cdc48-binding domains are essential for substrate retrotranslocation. Substrate processing by Dfm1 and Cdc48 complex requires the ubiquitin shuttle factors Rad23/Dsk2 and the multi-ubiquitination enzyme Ufd2. Our findings suggest a pathway in which a series of ubiquitin modifying factors recruit Dfm1 to resolve a stalled retrotranslocation intermediate due to the presence of a folded luminal domain.

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