The TRC8 E3 ligase ubiquitinates MHC class I molecules before dislocation from the ER

Martyn, Thomas; Boomen, Dick van den; Wiertz, Emmanuel J. H. J.; Drabkin, Harry A.; Gemmill, Robert M.; Lehner, Paul J.

doi:10.1084/jem20610oia22

Cited by 36 publications

(55 citation statements)

References 10 publications

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“…However, depletion of HRD1 does not rescue MHC I in US11-expressing cells, suggesting that US11 either recruits other E3 ligases or circumvents the need for a cellular ligase in MHC I dislocation. In contrast, US2-mediated MHC I dislocation uses a less-well characterized pathway-recruiting the TRC8 E3 ligase and signal peptide peptidase (9,16). Although endogenous UBE2J1, HRD1, Derlin 1, and p97 coprecipitate free HC10-reactive MHC I HCs, they did not bind conformational, W6/32-reactive MHC I.…”

Section: Discussionmentioning

confidence: 97%

“…RNAi screening was performed as previously described (9) and was targeted to 18 candidate E3 ligases, consisting of known ER membrane E3s and uncharacterized E3s with predicted transmembrane domains (31), as well as a library of 40 E2 ubiquitin-conjugating enzymes. Each gene was targeted with an siRNA pool of four oligonucleotides (final concentration 80 nM).…”

Section: Methodsmentioning

confidence: 99%

“…The E3 confers substrate specificity and is therefore the pivotal enzyme (5). In contrast to yeast, in which Hrd1p and Doa10p are the only two known ERAD E3s, at least five mammalian ERAD E3 ligases are known (HRD1, gp78, RMA1, TEB4, and TRC8) (6)(7)(8)(9) and further ERAD E3s may still be identified. The two mammalian orthologs of yeast Hrd1p, HRD1 (Synoviolin) and gp78 (AMFR), have distinct substrate specificities, exemplifying the increased complexity of mammalian ERAD (6,7).…”

mentioning

confidence: 99%

“…The human cytomegalovirus US2 and US11 gene products bind newly synthesized MHC I HCs and initiate their rapid dislocation to the cytosol for proteasomal degradation and helped define mammalian ERAD (14,15). US2-mediated MHC I degradation requires signal peptide peptidase and the E3 ligase TRC8 (9,16), whereas US11 utilizes a distinct Derlin 1, p97, and SEL1L-dependent pathway (17)(18)(19). HRD1 and gp78 are found in complex with Derlin I, although no functional role for these ligases has been demonstrated in US11-mediated MHC I ERAD (6,19).…”

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confidence: 99%

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HRD1 and UBE2J1 target misfolded MHC class I heavy chains for endoplasmic reticulum-associated degradation

Burr

Cano

Svobodova

et al. 2011

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

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120

118

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The assembly of MHC class I molecules is governed by stringent endoplasmic reticulum (ER) quality control mechanisms. MHC class I heavy chains that fail to achieve their native conformation in complex with β2-microglobulin (β2m) and peptide are targeted for ER-associated degradation. This requires ubiquitination of the MHC class I heavy chain and its dislocation from the ER to the cytosol for proteasome-mediated degradation, although the cellular machinery involved in this process is unknown. Using an siRNA functional screen in β2m-depleted cells, we identify an essential role for the E3 ligase HRD1 (Synoviolin) together with the E2 ubiquitin-conjugating enzyme UBE2J1 in the ubiquitination and dislocation of misfolded MHC class I heavy chains. HRD1 is also required for the ubiquitination and degradation of the naturally occurring hemochromatosisassociated HFE-C282Y mutant, which is unable to bind β2m. In the absence of HRD1, misfolded HLA-B27 accumulated in cells with a normal MHC class I assembly pathway, and HRD1 depletion prevented the appearance of low levels of cytosolic unfolded MHC I heavy chains. HRD1 and UBE2J1 associate in a complex together with non-β2m bound MHC class I heavy chains, Derlin 1, and p97 and discriminate misfolded MHC class I from conformational MHC Iβ2m-peptide heterotrimers. Together these data support a physiological role for HRD1 and UBE2J1 in the homeostatic regulation of MHC class I assembly and expression.

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Section: Discussionmentioning

confidence: 97%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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HRD1 and UBE2J1 target misfolded MHC class I heavy chains for endoplasmic reticulum-associated degradation

Burr

Cano

Svobodova

et al. 2011

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

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120

118

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“…However, the importance of TRC8 has been in question (51,52). Major histocompatibility complex (MHC) class I ubiquitination by TRC8 is also in response to specific disruption by cytomegalovirus US2, but not by US11, or by the lack of assembly under uninfected conditions, where HRD1 is responsible for degradation (30,43). US2 interacts with TRC8 luminal domain and recruits it to selected substrates, including MHC-I and several ␣-integrins (53).…”

Section: Discussionmentioning

confidence: 99%

Bag1 Co-chaperone Promotes TRC8 E3 Ligase-dependent Degradation of Misfolded Human Ether a Go-Go-related Gene (hERG) Potassium Channels

Hantouche

Williamson

Valinsky

et al. 2017

Journal of Biological Chemistry

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Edited by George N. DeMartinoCardiac long QT syndrome type 2 is caused by mutations in the human ether a go-go-related gene (hERG) potassium channel, many of which cause misfolding and degradation at the endoplasmic reticulum instead of normal trafficking to the cell surface. The Hsc70/Hsp70 chaperones assist the folding of the hERG cytosolic domains. Here, we demonstrate that the Hsp70 nucleotide exchange factor Bag1 promotes hERG degradation by the ubiquitin-proteasome system at the endoplasmic reticulum to regulate hERG levels and channel activity. Dissociation of hERG complexes containing Hsp70 and the E3 ubiquitin ligase CHIP requires the interaction of Bag1 with Hsp70, but this does not involve the Bag1 ubiquitin-like domain. The interaction with Bag1 then shifts hERG degradation to the membrane-anchored E3 ligase TRC8 and its E2-conjugating enzyme Ube2g2, as determined by siRNA screening. TRC8 interacts through the transmembrane region with hERG and decreases hERG functional expression. TRC8 also mediates degradation of the misfolded hERG-G601S disease mutant, but pharmacological stabilization of the mutant structure prevents degradation. Our results identify TRC8 as a previously unknown Hsp70-independent quality control E3 ligase for hERG.

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ERAD ubiquitin ligases

2010

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In eukaryotic cells terminally misfolded proteins of the secretory pathway are retarded in the endoplasmic reticulum (ER) and subsequently degraded in a ubiquitin-proteasome-dependent manner. This highly conserved process termed ER-associated protein degradation (ERAD) ensures homeostasis in the secretory pathway by disposing faulty polypeptides and preventing their deleterious accumulation and eventual aggregation in the cell. The focus of this paper is the functional description of membrane-bound ubiquitin ligases, which are involved in all critical steps of ERAD. In the end we want to speculate on how the modular architecture of these entities ensures the specificity of substrate selection and possibly accomplishes the transport of misfolded polypeptides from the ER into the cytoplasm.

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The TRC8 E3 ligase ubiquitinates MHC class I molecules before dislocation from the ER

Cited by 36 publications

References 10 publications

HRD1 and UBE2J1 target misfolded MHC class I heavy chains for endoplasmic reticulum-associated degradation

HRD1 and UBE2J1 target misfolded MHC class I heavy chains for endoplasmic reticulum-associated degradation

Bag1 Co-chaperone Promotes TRC8 E3 Ligase-dependent Degradation of Misfolded Human Ether a Go-Go-related Gene (hERG) Potassium Channels

ERAD ubiquitin ligases

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