Synoviolin/Hrd1, an E3 ubiquitin ligase, as a novel pathogenic factor for arthropathy

Amano, Tetsuya; Yamasaki, Satoshi; Yagishita, Naoko; Tsuchimochi, Kaneyuki; Shin, Hiroshi; Kikuchi, Kôichi; Aratani, Satoko; Fujita, Hidetoshi; Zhang, Lei; Ikeda, Rie; Fujii, Ryoji; Miura, Naoki; Komiya, Setsuro; Nishioka, Kusuki; Maruyama, Ikuro; Fukamizu, Akiyoshi; Nakajima, Takeshi

doi:10.1101/gad.1096603

Cited by 172 publications

(241 citation statements)

References 56 publications

(43 reference statements)

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“…Moreover, Usa1p appears to play a crucial role in regulation of Hrd1p, preventing cellular toxicity by curbing Hrd1p activity when appropriate. The importance of these Usa1-type regulators of the HRD complex will be of interest both in normal circumstances and in cases where the Hrd1p ligase is elevated or overabundant, such as in rheumatoid arthritis (32), or in cases where ER stress elevates the levels of the HRD complex (33).…”

Section: Discussionmentioning

confidence: 99%

Usa1p Is Required for Optimal Function and Regulation of the Hrd1p Endoplasmic Reticulum-associated Degradation Ubiquitin Ligase

Carroll

Hampton

2010

Journal of Biological Chemistry

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Usa1p is a recently discovered member of the HRD ubiquitin ligase complex. The HRD pathway is a conserved route of ubiquitin-dependent, endoplasmic reticulum (ER)-associated degradation (ERAD) of numerous lumenal (ERAD-L) and membrane-anchored (ERAD-M) substrates. We have investigated Usa1p to understand its importance in HRD complex action. Usa1p was required for the optimal function of the Hrd1p E3 ubiquitin ligase; its loss caused deficient degradation of both membrane-associated and lumenal proteins. Furthermore, Usa1p functioned in regulation of Hrd1p by two mechanisms. First, Hrd1p self-degradation, which serves to limit the levels of uncomplexed E3, is absolutely dependent on Usa1p and the ubiquitin-like (Ubl) domain of Usa1p. We found that Usa1p allows Hrd1p degradation by promoting trans interactions between Hrd1p molecules. The Ubl domain of Usa1p was required specifically for Hrd1p self-ubiquitination but not for degradation of either ERAD-L or ERAD-M substrates. In addition, Usa1p was able to attenuate the activity-dependent toxicity of Hrd1p without compromising substrate degradation, indicating a separate role in ligase regulation that operates in parallel to stability control. Many of the described actions of Usa1p are distinct from those of Der1p, which is recruited to the HRD complex by Usa1p. Thus, this novel, conserved factor is broadly involved in the function and regulation of the HRD pathway of ERAD. ER3 -associated degradation (ERAD) is a conserved process by which eukaryotic cells target and degrade ER-resident proteins by the ubiquitin-proteasome pathway. ERAD pathways play a major role in the destruction of misfolded or unassembled ER proteins, including both lumenal and integralmembrane substrates. In addition, normal proteins are regulated by this pathway, the most prominent case being the sterol pathway-regulated degradation of HMG-CoA reductase in both yeast and mammals (1, 2). Eukaryotic ERAD is brought about by the action of multiple pathways of ubiquitin-mediated degradation that operate at the ER surface (3, 4).Covalent addition of ubiquitin to proteins brings about their recognition and degradation by the cytosolic 26S proteasome. Protein ubiquitination occurs by a cascade of enzymes that add 7.6-kDa ubiquitin to the targeted protein. The E1 ubiquitinactivating enzyme first forms a high energy bond with ubiquitin in an ATP-dependent reaction, and then the ubiquitin is transferred to an E2, or ubiquitin-conjugating enzyme. E2-bound ubiquitin is next transferred from the charged E2 to the target protein by the action of a ubiquitin ligase, or E3, that ensures specificity of transfer to the proper degradation substrate. The action of the E3 is iterative, causing the construction of a substrate-bound multiubiquitin chain that is recognized by the 26S proteasome (5). Several E3 ubiquitin ligases are involved in the destruction of ER proteins. Thus, ERAD is a composite of ubiquitination pathways with distinct ligases that use both separate and common components to effect recognition,...

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Section: Discussionmentioning

confidence: 99%

Usa1p Is Required for Optimal Function and Regulation of the Hrd1p Endoplasmic Reticulum-associated Degradation Ubiquitin Ligase

Carroll

Hampton

2010

Journal of Biological Chemistry

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“…There are two mammalian proteins that are structurally and functionally related to yeast Hrd1p, gp78/autocrine motility factor receptor and HRD1/Synoviolin (Fang et al, 2001;Amano et al, 2003;Kikkert et al, 2004). Gp78 was originally identified as a 78-kDa cell surface receptor for a tumor cell autocrine motility factor that promotes tumor metastasis (Nabi and Raz, 1987).…”

Section: Introductionmentioning

confidence: 99%

Gp78 Cooperates with RMA1 in Endoplasmic Reticulum-associated Degradation of CFTRΔF508

Morito

Hirao

Oda

et al. 2008

MBoC

209

208

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Misfolded or improperly assembled proteins in the endoplasmic reticulum (ER) are exported into the cytosol and degraded via the ubiquitin-proteasome pathway, a process termed ER-associated degradation (ERAD). Saccharomyces cerevisiae Hrd1p/Der3p is an ER membrane-spanning ubiquitin ligase that participates in ERAD of the cystic fibrosis transmembrane conductance regulator (CFTR) when CFTR is exogenously expressed in yeast cells. Two mammalian orthologues of yeast Hrd1p/Der3p, gp78 and HRD1, have been reported. Here, we demonstrate that gp78, but not HRD1, participates in ERAD of the CFTR mutant CFTR⌬F508, by specifically promoting ubiquitylation of CFTR⌬F508. Domain swapping experiments and deletion analysis revealed that gp78 binds to CFTR⌬F508 through its ubiquitin binding region, the so-called coupling of ubiquitin to ER degradation (CUE) domain. Gp78 polyubiquitylated in vitro an N-terminal ubiquitin-glutathione-S-transferase (GST)-fusion protein, but not GST alone. This suggests that gp78 recognizes the ubiquitin that is already conjugated to CFTR⌬F508 and catalyzes further polyubiquitylation of CFTR⌬F508 in a manner similar to that of a multiubiquitin chain assembly factor (E4). Furthermore, we revealed by small interfering RNA methods that the ubiquitin ligase RMA1 functioned as an E3 enzyme upstream of gp78. Our data demonstrates that gp78 cooperates with RMA1 with E4-like activity in the ERAD of CFTR⌬F508.

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“…It was independently identified as being up-regulated in synoviocytes from rheumatoid arthritis (RA) patients (8). Transgenic mice overexpressing HRD1 developed spontaneous joint pathology characterized by synoviocyte hyperplasia and invasion into cartilage and bone, whereas heterozygous HRD1 knock-out animals showed decreased susceptibility and severity in two arthritis models (8).…”

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confidence: 99%

Ubiquitin Ligase Substrate Identification through Quantitative Proteomics at Both the Protein and Peptide Levels

Lee

Hammerle

Andrews

et al. 2011

Journal of Biological Chemistry

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Background: Identification of ubiquitin ligase substrates remains an unmet challenge. Results: Two proteomic strategies were used to identify novel substrates of the E3 ligase HRD1. Conclusion: These methods identified populations of substrates enriched for potential targets of endoplasmic reticulumassociated degradation. Significance: This approach should be broadly useful for E3 ligase substrate identification, and the identified substrates provide insight into the role of HRD1 in disease.

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Synoviolin/Hrd1, an E3 ubiquitin ligase, as a novel pathogenic factor for arthropathy

Cited by 172 publications

References 56 publications

Usa1p Is Required for Optimal Function and Regulation of the Hrd1p Endoplasmic Reticulum-associated Degradation Ubiquitin Ligase

Usa1p Is Required for Optimal Function and Regulation of the Hrd1p Endoplasmic Reticulum-associated Degradation Ubiquitin Ligase

Gp78 Cooperates with RMA1 in Endoplasmic Reticulum-associated Degradation of CFTRΔF508

Ubiquitin Ligase Substrate Identification through Quantitative Proteomics at Both the Protein and Peptide Levels

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