Der1 promotes movement of misfolded proteins through the endoplasmic reticulum membrane

Mehnert, Martin; Sommer, Thomas; Jarosch, Ernst

doi:10.1038/ncb2882

Cited by 140 publications

(127 citation statements)

References 52 publications

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“…Despite clear evidence that derlins interact with aberrant polypeptides, directing them from the ER lumen, or the plane of the ER membrane, towards ubiquitylation and extraction [52][53][54][55][56], the exact molecular mechanism of dislocation is still debated. Whereas initially yeast Der1 was suggested to act as a receptor for ERAD substrates [39], subsequently human Derlin1 was hypothesized to form a protein-conducting dislocation channel [50,51].…”

Section: What Has Identification Of Derlins As Rhomboid Pseudoproteasmentioning

confidence: 99%

Inactive rhomboid proteins: New mechanisms with implications in health and disease

Lemberg

Adrain

2016

Seminars in Cell & Developmental Biology

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Rhomboids, proteases containing an unusual membrane-integral serine protease active site, were first identified in Drosophila, where they fulfill an essential role in epidermal growth factor receptor signaling, by cleaving membrane-tethered growth factor precursors. It has recently become apparent that eukaryotic genomes harbor conserved catalytically inactive rhomboid protease homologs, including derlins and iRhoms. Here we highlight how loss of proteolytic activity was followed in evolution by impressive functional diversification, enabling these pseudoproteases to fulfill crucial roles within the secretory pathway, including protein degradation, trafficking regulation, and inflammatory signaling. We distil the current understanding of the roles of rhomboid pseudoproteases in development and disease.

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Section: What Has Identification Of Derlins As Rhomboid Pseudoproteasmentioning

confidence: 99%

Inactive rhomboid proteins: New mechanisms with implications in health and disease

Lemberg

Adrain

2016

Seminars in Cell & Developmental Biology

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“…Here several components have been discussed as pore forming components and recently major contribution in respect to Der1 (Derlin1-3 in mammals) proteins and the E3 ligases were published (Mehnert et al, 2014;Stein et al, 2014). Nevertheless, the Sec61-complex, which was initially discussed as bidirectional channel is still favored for being the ERAD re-translocation pore in some publications.…”

Section: The Sder1-complex Of Diatomsmentioning

confidence: 99%

Protein import into complex plastids: Cellular organization of higher complexity

Maier

Zauner

Hempel

2015

European Journal of Cell Biology

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“…Derlin-1's role within the US11 system is difficult to study because Derlin-1 depletion dissociates viral US11 from TMEM129, disrupting ubiquitination, recognition, and dislocation. If Derlin-1 is part of the retrotranslocon (25,26), US11 binding might directly impact on channel opening and substrate dislocation.…”

Section: Us11 Tagged With a Mhc-i Cytosolic Tail Is Rapidly Degraded Bymentioning

confidence: 99%

TMEM129 is a Derlin-1 associated ERAD E3 ligase essential for virus-induced degradation of MHC-I

Boomen

Timms

Grice

et al. 2014

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

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The US11 gene product of human cytomegalovirus promotes viral immune evasion by hijacking the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway. US11 initiates dislocation of newly translocated MHC I from the ER to the cytosol for proteasome-mediated degradation. Despite the critical role for ubiquitin in this degradation pathway, the responsible E3 ligase is unknown. In a forward genetic screen for host ERAD components hijacked by US11 in near-haploid KBM7 cells, we identified TMEM129, an uncharacterized polytopic membrane protein. TMEM129 is essential and rate-limiting for US11-mediated MHC-I degradation and acts as a novel ER resident E3 ubiquitin ligase. TMEM129 contains an unusual cysteine-only RING with intrinsic E3 ligase activity and is recruited to US11 via Derlin-1. Together with its E2 conjugase Ube2J2, TMEM129 is responsible for the ubiquitination, dislocation, and subsequent degradation of US11-associated MHC-I. US11 engages two degradation pathways: a Derlin-1/TMEM129-dependent pathway required for MHC-I degradation and a SEL1L/HRD1-dependent pathway required for "free" US11 degradation. Our data show that TMEM129 is a novel ERAD E3 ligase and the central component of a novel mammalian ERAD complex. P roteins inserted into the endoplasmic reticulum (ER) must fold and acquire their native state before further trafficking through the secretory pathway (1, 2). To avoid the toxicity associated with misfolded gene products, all proteins must pass the ER quality-control checkpoint. Misfolded proteins are rejected and dislocated across the ER-membrane for cytosolic proteasome degradation in a process known as ER-associated degradation (ERAD). ERAD degrades misfolded and unassembled proteins and regulates turnover of ER-resident proteins (3).Ubiquitination of the protein substrate provides a critical step in protein dislocation (4). The RING family constitutes the largest family of E3 ligases, including those involved in ERAD (5). The RING domain creates a binding platform for the E2 conjugase and consists of two zinc atoms coordinated in a cross-brace motif via interspersed cysteine (C) and histidine (H) residues in a C3HC4, C3H2C3, or C4HC3 conformation (5). Most ERAD E3 ligases are integral membrane proteins; they form the core of the ERAD machinery, nucleating functionally distinct ERAD complexes. The mammalian system is more complex than yeast and has undergone an expansion of the ERAD E3 ligase family, with the Hrd1p homologs Hrd1 and Gp78, the Doa10p homolog MARCH6, RNF5, TRC8, and CHIP (3, 4).Many pathogens appropriate the ubiquitin-proteasome system, particularly to degrade components of the host immune system (6, 7). The human cytomegalovirus (HCMV) US2 and US11 gene products have been instrumental in studies of the mammalian ERAD system. These viral proteins hijack separate components of the ERAD system to degrade MHC-I, thus preventing cytotoxic T lymphocyte recognition of infected cells (8,9). US2 appropriates the TRC8 E3 ubiquitin ligase (10), whereas dislocation induced by US1...

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Der1 promotes movement of misfolded proteins through the endoplasmic reticulum membrane

Cited by 140 publications

References 52 publications

Inactive rhomboid proteins: New mechanisms with implications in health and disease

Inactive rhomboid proteins: New mechanisms with implications in health and disease

Protein import into complex plastids: Cellular organization of higher complexity

TMEM129 is a Derlin-1 associated ERAD E3 ligase essential for virus-induced degradation of MHC-I

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