Herp coordinates compartmentalization and recruitment of HRD1 and misfolded proteins for ERAD

Leitman, Julia; Shenkman, Marina; Gofman, Yana; Shtern, Navit Ogen; Ben‐Tal, Nir; Hendershot, Linda M.; Lederkremer, Gerardo Z.

doi:10.1091/mbc.e13-06-0350

Cited by 72 publications

(92 citation statements)

References 48 publications

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“…In fact, they are part of a functional complex that binds unfolded polypeptide chains in the mammalian ER shielding their interaction with CNX/CRT (48) and play well established roles in secretory proteins quality control (53)(54)(55). HERP is an unconventionally short-living ERAD factor that acts as a scaffold for assembly of supramolecular membrane embedded complexes regulating dislocation of misfolded polypeptides from the ER lumen into the cytosol for proteasomal degradation (56). It has been proposed that elevation of HERP levels both by inducing its expression or by slowing-down its turnover might be part of the first line of cellular defense to accumulation of unfolded proteins in processes that have been collectively defined as ERAD tuning (57).…”

Section: Discussionmentioning

confidence: 99%

Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides

Bergmann

Fregno

Fumagalli

et al. 2018

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides

Bergmann

Fregno

Fumagalli

et al. 2018

Journal of Biological Chemistry

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“…However, in some cases, misfolded proteins are retained in the ER and accumulate in a suborganelle that contains misfolded ERresident proteins and that is known as the ERderived quality-control compartment (ERQC) (Kamhi-Nesher et al 2001). Recently, the ERQC was shown to serve as an intermediate stage for ERAD substrates, indicating that this suborganelle plays a cytoprotective role (Leitman et al 2014). …”

Section: Aggregate Deposition Sites-beyond Aggresomesmentioning

confidence: 99%

Protein Quality Control in Health and Disease

Dubnikov

Ben‐Gedalya

Cohen

2016

Cold Spring Harb Perspect Biol

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Maintaining functional protein homeostasis ( proteostasis) is a constant challenge in the face of limited protein-folding capacity, environmental threats, and aging. Cells have developed several quality-control mechanisms that assist nascent polypeptides to fold properly, clear misfolded molecules, respond to the accumulation of protein aggregates, and deposit potentially toxic conformers in designated sites. Proteostasis collapse can lead to the development of diseases known as proteinopathies. Here we delineate the current knowledge on the different layers of protein quality-control mechanisms at the organelle and cellular levels with an emphasis on the prion protein (PrP). We also describe how protein quality control is integrated at the organismal level and discuss future perspectives on utilizing proteostasis maintenance as a strategy to develop novel therapies for the treatment of proteinopathies.

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“…An improperly assembled AtHrd1a thus could be degraded by an AtHrd1a-independent ERAD pathway. It is interesting that both the yeast Usa1 and mammalian HERP are known to interact directly with their corresponding ER membraneanchored E3 ligases and are thought to regulate the stability and/or oligomerization of their interacting E3 ligases (43)(44)(45). Despite the absence of sequence homology with Usa1 and HERP, both of which carry an ubiquitin-like domain at the N terminus, EBS7 could be a functional homolog of Usa1/HERP.…”

Section: Ebs7 Is a Plant-specific Er Membrane-anchored Component Of Anmentioning

confidence: 99%

EBS7 is a plant-specific component of a highly conserved endoplasmic reticulum-associated degradation system in Arabidopsis

Liu

Zhang

Wang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Endoplasmic reticulum (ER)-associated degradation (ERAD) is an essential part of an ER-localized protein quality-control system for eliminating terminally misfolded proteins. Recent studies have demonstrated that the ERAD machinery is conserved among yeast, animals, and plants; however, it remains unknown if the plant ERAD system involves plant-specific components. Here we report that the Arabidopsis ethyl methanesulfonate-mutagenized brassinosteroidinsensitive 1 suppressor 7 (EBS7) gene encodes an ER membranelocalized ERAD component that is highly conserved in land plants. Loss-of-function ebs7 mutations prevent ERAD of brassinosteroid insensitive 1-9 (bri1-9) and bri1-5, two ER-retained mutant variants of the cell-surface receptor for brassinosteroids (BRs). As a result, the two mutant receptors accumulate in the ER and consequently leak to the plasma membrane, resulting in the restoration of BR sensitivity and phenotypic suppression of the bri1-9 and bri1-5 mutants. EBS7 accumulates under ER stress, and its mutations lead to hypersensitivity to ER and salt stresses. EBS7 interacts with the ER membrane-anchored ubiquitin ligase Arabidopsis thaliana HMGCoA reductase degradation 1a (AtHrd1a), one of the central components of the Arabidopsis ERAD machinery, and an ebs7 mutation destabilizes AtHrd1a to reduce polyubiquitination of bri1-9. Taken together, our results uncover a plant-specific component of a plant ERAD pathway and also suggest its likely biochemical function.is an integral part of an ER-mediated protein quality-control system in eukaryotes, which permits export of only correctly folded proteins but retains misfolded proteins in the ER for repair via additional folding attempts or removal through ERAD. Genetic and biochemical studies in yeast and mammalian cells have revealed that the core ERAD machinery is highly conserved between yeast and mammals and that ERAD involves four tightly coupled steps: substrate selection, retrotranslocation through the ER membrane, ubiquitination, and proteasome-mediated degradation (1, 2).Because the great majority of secretory/membrane proteins are glycosylated in the ER, diversion of most ERAD substrates from their futile folding cycles into ERAD is initiated through progressive mannose trimming of their asparagine-linked glycans (N-glycans) by ER/Golgi-localized class I mannosidases, including homologous to α-mannosidase 1 (Htm1) and its mammalian homologs ER degradation-enhancing α-mannosidase-like proteins (EDEMs) (3). The processed glycoproteins are captured by two ER resident proteins, yeast amplified in osteosarcoma 9 (OS9 in mammals) homolog (Yos9) and HMG-CoA reductase degradation 3 (Hrd3) [suppressor/enhancer of Lin-12-like (SEL1L) in mammals], which recognize the mannose-trimmed N-glycans and surface-exposed hydrophobic amino acid residues, respectively (4, 5). The selected ERAD clients are delivered to an ER membraneanchored ubiquitin ligase (E3), which is the core component of the ERAD machinery (6), for polyubiquitination. Yeast has two known ERAD E3 lig...

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Herp coordinates compartmentalization and recruitment of HRD1 and misfolded proteins for ERAD

Cited by 72 publications

References 48 publications

Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides

Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides

Protein Quality Control in Health and Disease

EBS7 is a plant-specific component of a highly conserved endoplasmic reticulum-associated degradation system in Arabidopsis

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