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SVIP interacts with Derlin1 and regulates ER‐associated degradation
Author(s) -
Ballar Petek,
Shen Yuxian,
Zhong Yongwang,
Nagahama Masami,
Tagaya Mitsuo,
Apostolou Andria,
Fang Shengyun
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a1023-d
Subject(s) - endoplasmic reticulum associated protein degradation , endoplasmic reticulum , microbiology and biotechnology , ubiquitin , tunicamycin , unfolded protein response , immunoprecipitation , biology , downregulation and upregulation , biochemistry , gene
Production of misfolded proteins in the endoplasmic reticulum (ER) underlies pathogenesis of many diseases. Cells utilize a process, called ER‐associated degradation (ERAD) to eliminate misfolded ER proteins, thereby protecting against the toxicity of the defective proteins. However, the molecular mechanisms underlying the process of ERAD remain to be fully understood. Here, we report that the SVIP is specifically and highly expressed in mouse brain as revealed by mouse multi‐tissue blotting. By Opti‐Prep density gradient fractionation, we demonstrated that SVIP is co‐fractionated with ERAD machineries, including Derlin1, Hrd1, and gp78. Co‐immunoprecipitation shows that SVIP strongly interacts with Derlin1 and p97/VCP, but weakly with Hrd1 and gp78. SVIP is anchored to the ER membrane probably via myristoylation, since mutation of the putative myristoylation site impaired its ER localization. Further, we found that SVIP is upregulated by tunicamycin‐induced ER stress both at mRNA and protein levels. Functionally, SVIP enhances the loading of polyubiquitinated proteins to p97/VCP, suggesting that SVIP may play a role in coupling ubiquitination with retrotranslocation of misfolded proteins during ERAD. Consistently, silencing of SVIP expression by RNA interference stabilizes ERAD substrate tyrosinase(C89R). These results suggest that SVIP may facilitate the coupling of ubiquitination with retrotranslocation during ERAD and might play a protective role in brain.