Human HRD1 protects against ER stress‐induced apoptosis through ER‐associated degradation1

FEBS Letters

Nomura, Yasuyuki¹  Uesugi, Mai¹  Kaneko, Masayuki¹  Niinuma, Yoshifumi¹  Ishiguro, Masataro¹ 

[1] Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan

关键词: Endoplasmic reticulum;    Endoplasmic reticulum-associated degradation;    Hrd1p;    Ubiquitin ligase;    Unfolded protein response;    IRE1;    ER;    endoplasmic reticulum;    ERAD;    ER-associated degradation;    HRD;    hydroxymethylglutaryl reductase degradation;    UPR;    unfolded protein response;    E3;    ubiquitin-protein ligase;    E2;    ubiquitin-conjugating enzyme;    RT-PCR;    reverse transcription-polymerase chain reaction;    UBL;    ubiquitin-like;    SEL;    suppressor/enhancer of lin-12;    PS;    presenilin;    FAD;    familial Alzheimer's disease;   

DOI  :  10.1016/S0014-5793(02)03660-8

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

Stresses that impair the function of the endoplasmic reticulum (ER) lead to an accumulation of unfolded protein in the ER. Under these conditions, the expression of a variety of genes involved in preventing the accumulation of the unfolded proteins is induced. Yeast Hrd1p is an ER stress-inducible ER membrane protein that acts as a ubiquitin ligase (E3) with a RING finger motif and plays a role in the ubiquitination of proteins in the ER. We report here the identification and characterization of a human homolog to yeast Hrd1p. The predicted structures are highly conserved from yeast to humans. Indeed, human HRD1 was localized to the ER and ubiquitinated its substrates. Furthermore, it was found that human HRD1 was up-regulated by ER stress via IRE1 and ATF6, which are ER stress transducers. Interestingly, 293 cells stably expressing wild-type HRD1, but not the C329S mutant, afforded resistance to ER stress-induced apoptosis. These results suggest that the production of HRD1 is up-regulated to protect against ER stress-induced apoptosis by degrading unfolded proteins accumulated in the ER.

【 授权许可】

Unknown