Ubiquilin and p97/VCP bind erasin, forming a complex involved in ERAD

Lim, Precious J.; Danner, Rebecca; Liang, Jing; Doong, Howard; Harman, Christine; Srinivasan, Deepa; Rothenberg, Cara; Wang, Hongmin; Ye, Yihong; Fang, Shengyun; Monteiro, Mervyn J.

doi:10.1083/jcb.200903024

Cited by 131 publications

(150 citation statements)

References 63 publications

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“…), chain elongation factors (Ufd2, E4 ubiquitin ligase), and deubiquitinases (YOD1, Ataxin-3, VCIP135) (Liang et al 2006;Mueller et al 2008;Schuberth and Buchberger 2008;Ernst et al 2009). Ubiquitinated substrates are transferred to the proteasome by shuttle proteins, known as HR23A/B or Ubiquilin-1 (Rad23 and Dsk2 in yeast), which contain ubiquitinassociated (UBA) and ubiquitin-like (UBL) domains that bind to polyubiquitin chains and the proteasome subunits (Rpn10/13, Rpt5), respectively (Deveraux et al 1994;Lam et al 2002;Raasi and Wolf 2007;Husnjak et al 2008;Finley 2009;Lim et al 2009). …”

Section: Retrotranslocation and Degradationmentioning

confidence: 99%

Protein Folding and Quality Control in the ER

Araki

Nagata

2011

Cold Spring Harbor Perspectives in Biology

317

285

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The endoplasmic reticulum (ER) uses an elaborate surveillance system called the ER quality control (ERQC) system. The ERQC facilitates folding and modification of secretory and membrane proteins and eliminates terminally misfolded polypeptides through ER-associated degradation (ERAD) or autophagic degradation. This mechanism of ER protein surveillance is closely linked to redox and calcium homeostasis in the ER, whose balance is presumed to be regulated by a specific cellular compartment. The potential to modulate proteostasis and metabolism with chemical compounds or targeted siRNAs may offer an ideal option for the treatment of disease.

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Section: Retrotranslocation and Degradationmentioning

confidence: 99%

Protein Folding and Quality Control in the ER

Araki

Nagata

2011

Cold Spring Harbor Perspectives in Biology

317

285

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“…Ubqln binds ubiquitinated proteins through the UBA, at the same time binding the proteasome through the UBL; it appears to act as a scaffold to facilitate proteasomal degradation of ubiquitinated proteins that have been exported from the ER (24,25). This function could explain most of the proposed functions of Ubqln, such as regulation of autophagy, unfolded protein response, and interaction with both poly-alanine and poly-glutamine expanded proteins (21,22,(27)(28)(29)(30)41).…”

Section: Discussionmentioning

confidence: 98%

“…Recently, Ubqln has been shown to play a role in a variety of other cellular processes, including autophagy, ER-associated protein degradation (ERAD) and receptor trafficking, presumably by regulating the abundance of proteins implicated in these events (21)(22)(23)(24)(25)(26)(27)(28)(29)(30). Furthermore, UBQLN is one member of a family of at least five proteins (UBQLN1, UBQLN2, UBQLN3, UBQLN4, and UBQLNL) that share a high degree of similarity at the level of both amino acid and domain structure.…”

mentioning

confidence: 99%

Ubiquitination, localization, and stability of an anti-apoptotic BCL2-like protein, BCL2L10/BCLb, are regulated by Ubiquilin1

Beverly

Lockwood

Shah

et al. 2012

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

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We have previously shown that all six members of the anti-apoptotic BCL2 gene family can cooperate with (myelocytomatosis oncogene) MYC in a mouse model of leukemia, but three of them are significantly less potent contributors to leukemogenicity than the other three. The protein encoded by one of these less potent genes, BCL2L10∕BCLb, was recently shown to vary dramatically in many primary human cancers by immunohistochemistry, and the protein levels were inversely correlated with survival in patients with several cancer types. We examined BCLb mRNA in a panel of human cancer cell lines and did not observe the extensive variation in mRNA that would be required to explain the vast differences in protein levels. We found that the levels of BCLb protein diminish quickly after inhibition of protein synthesis with cycloheximide, so we searched for interacting proteins that might affect posttranslational stability of BCLb. Using a variety of approaches, including immunoaffinity and mass spectrometry, we identified a protein, Ubiquilin1 (Ubqln), that specifically interacts with BCLb, and not with other anti-apoptotic BCL2-like proteins. Ubqln stabilizes BCLb protein, while also promoting monoubiquitination on multiple lysine residues and relocation to the cytosol. Furthermore, primary lung adencarcinomas have more Ubqln mRNA than normal adjacent lung tissue, and higher Ubqln mRNA levels are associated with shorter survival of lung cancer patients, suggesting that potentiation of the anti-apoptotic potential of BCLb through regulation of its stability by Ubqln may be an important factor in tumor progression.

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“…Although it was postulated that UBQLN1 participates in spermiogenesis, in vivo support for this is still pending. UBQLN1 and its homologue UBQLN2 form a complex with p97/VCP and erasin, both of which are central components of the ER dislocation machinery (40). UBE2J1, UBQLN1, and SPEM1 may function co-operatively during the removal of cytoplasm from elongating spermatids.…”

Section: Discussionmentioning

confidence: 99%