Stringent requirement for HRD1, SEL1L, and OS-9/XTP3-B for disposal of ERAD-LS substrates

Bernasconi, Riccardo; Galli, Carmela; Calanca, Verena; Nakajima, Takeshi; Molinari, Maurizio

doi:10.1083/jcb.200910042

Cited by 165 publications

(173 citation statements)

References 77 publications

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“…Degradation of ER-transmembrane proteins can be Sel1L-Hrd1-independent because of functional redundancy among the ERAD complexes (27). Finally, pointing to a dispensable role of Sel1L in ER homeostasis in vivo, knockdown of Sel1L in cultured cells fails to induce UPR (28,29) and deletion of Hrd3/Sel1 in the fly has no effect on eye size (30).…”

Section: Significancementioning

confidence: 99%

Sel1L is indispensable for mammalian endoplasmic reticulum-associated degradation, endoplasmic reticulum homeostasis, and survival

Sun

Shi

Han

et al. 2014

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

163

239

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Significance This study provides insights into the physiological role of Sel1L, an adaptor protein for the ubiquitin ligase Hrd1 in endoplasmic reticulum-associated degradation (ERAD). Using both animal and cell models, this study provides unequivocal evidence for an indispensable role of Sel1L in Hrd1 stabilization, mammalian ERAD, endoplasmic reticulum homeostasis, protein translation, and cellular and organismal survival. Moreover, generation of inducible knockout mouse and cell models deficient in both Sel1L and Hrd1 provides an unprecedented opportunity to elucidate the functional importance of this key branch of ERAD in vivo and to identify its physiological substrates.

show abstract

Section: Significancementioning

confidence: 99%

Sel1L is indispensable for mammalian endoplasmic reticulum-associated degradation, endoplasmic reticulum homeostasis, and survival

Sun

Shi

Han

et al. 2014

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

163

239

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“…E3 ligases confer specificity of ubiquitin conjugation by interacting with the substrates to promote efficient ubiquitin transfer. While some ER‐resident E3s like Hrd1 (Hampton et al , 1996; Bernasconi et al , 2010; Kanehara et al , 2010; Christianson et al , 2011) seem to accommodate a broad range of substrates, others appear to be more selective including TRC8 (Stagg et al , 2009) and RNF170 (Lu et al , 2011). We identified the RING‐finger protein CGRRF1 as an Evi‐binding E3 ligase that modulates the abundance of Evi.…”

Section: Discussionmentioning

confidence: 99%

ERAD‐dependent control of the Wnt secretory factor Evi

et al. 2018

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Active regulation of protein abundance is an essential strategy to modulate cellular signaling pathways. Within the Wnt signaling cascade, regulated degradation of β‐catenin by the ubiquitin‐proteasome system (UPS) affects the outcome of canonical Wnt signaling. Here, we found that abundance of the Wnt cargo receptor Evi (Wls/GPR177), which is required for Wnt protein secretion, is also regulated by the UPS through endoplasmic reticulum (ER)‐associated degradation (ERAD). In the absence of Wnt ligands, Evi is ubiquitinated and targeted for ERAD in a VCP‐dependent manner. Ubiquitination of Evi involves the E2‐conjugating enzyme UBE2J2 and the E3‐ligase CGRRF1. Furthermore, we show that a triaging complex of Porcn and VCP determines whether Evi enters the secretory or the ERAD pathway. In this way, ERAD‐dependent control of Evi availability impacts the scale of Wnt protein secretion by adjusting the amount of Evi to meet the requirement of Wnt protein export. As Wnt and Evi protein levels are often dysregulated in cancer, targeting regulatory ERAD components might be a useful approach for therapeutic interventions.

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“…The E3 ubiquitin ligase Hrd1 is required for the ubiquitination and degradation of many ERAD substrates (8,(24)(25)(26)(27)(28)…”

Section: Resultsmentioning

confidence: 99%

“…Knockdown of EDEM1, Bip, and grp94 all enhanced fluorescence. Finally, two ER localized lectins, XTP3-B and osteosarcoma amplified 9 (OS-9), which are required for the recognition of many glycosylated ERAD substrates (8,24,33), only showed a marginal effect on fluorescence inhibition. This may be due to redundancy between the lectins.…”

Section: Ss-ddvenus Asmentioning

confidence: 99%

Deglycosylation-dependent fluorescent proteins provide unique tools for the study of ER-associated degradation

Grotzke

Lu²,

Cresswell

2013

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

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Endoplasmic reticulum-associated degradation (ERAD) is a constitutive process that identifies misfolded proteins in the ER and shuttles them to the cytosol, where they can be degraded by the proteasome. The accumulation of misfolded proteins can be catastrophic at both the cellular and organismal level. Although the players involved and mechanistic details of ERAD are being characterized, much remains to be learned. Because of the complexity of the pathway, experimental studies generally require labor-intensive biochemical techniques. Here, we report the development of a system to analyze ERAD based on mutants of split or intact Venus fluorescent protein for which fluorescence depends on enzymatic deglycosylation. We have generated variants that only become fluorescent when they are first glycosylated in the ER and subsequently deglycosylated after retrotranslocation into the cytosol. The E3 ubiquitin ligase HMG-coA reductase degradation 1 homolog (Hrd1) and, consistent with the demonstrated glycosylation/deglycosylation requirement, the cytosolic deglycosylating enzyme peptide:N′glycanase are both required for fluorescence. Furthermore, although these deglycosylation-dependent fluorescent proteins are themselves ERAD substrates, they can also be fused to additional ERAD substrates to interrogate substrate-specific pathways. To validate the system we performed a genomewide siRNA screen that successfully identified known ERAD factors such as Hrd1; homocysteine-inducible, endoplasmic reticulum stress-inducible, ubiquitin-like domain member 1 (HERP); sel-1 suppressor of lin-12-like (SEL1L); and p97. These tools should greatly facilitate the identification of ERAD components and investigation of the mechanisms involved in this critical pathway.

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Stringent requirement for HRD1, SEL1L, and OS-9/XTP3-B for disposal of ERAD-LS substrates

Abstract: Soluble ERAD substrates require the Hrd1 E3 ligase for degradation compared with membrane-anchored peptides that use GP78.

Cited by 165 publications

References 77 publications

Sel1L is indispensable for mammalian endoplasmic reticulum-associated degradation, endoplasmic reticulum homeostasis, and survival

Sel1L is indispensable for mammalian endoplasmic reticulum-associated degradation, endoplasmic reticulum homeostasis, and survival

ERAD‐dependent control of the Wnt secretory factor Evi

Deglycosylation-dependent fluorescent proteins provide unique tools for the study of ER-associated degradation

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