title: ER stress differentially regulates the stabilities of ERAD ubiquitin ligases and their substrates.
abstract: Endoplasmic reticulum (ER) stress-induced accumulation of misfolded proteins in the ER stimulates the ER-associated degradation (ERAD) process. ERAD in turn eliminates those misfolded proteins. Upregulation of ubiquitination enzymes is an essential mechanism by which ER stress enhances ERAD. However, ectopic overexpression of ubiquitination enzymes often fails to increase, and sometimes, inhibits ERAD. To further understand how ER stress regulates ERAD, we studied the effects of ER stress on ubiquitin ligase (E3) gp78-mediated ERAD and on the stabilities of gp78 and another ERAD E3 Hrd1. The results showed that ER stress-inducing agent tunicamycin significantly enhanced ERAD in cells that either express endogenous or overexpress gp78. Importantly, ER stress could increase ERAD even when new protein synthesis was inhibited by cycloheximide. Surprisingly, tunicamycin treatment stabilized gp78, an established ERAD E3 and an ERAD substrate as well, for up to 8h. By contrast, ER stress had little effects on the stability of another E3 Hrd1 except that it reduced the total ubiquitination level of Hrd1. Our data suggest that ER stress differentially regulates the stabilities of ERAD E3s and their substrates, which may represent a novel mechanism by which ER stress increases ERAD.
authors.affiliation: Institute of Clinical Pharmacology, Anhui Medical University, Hefei 230032, PR China.
authors.forename: Yuxian
authors.initials: Y
authors.lastname: Shen
authors.forename: Petek
authors.initials: P
authors.lastname: Ballar
authors.forename: Andria
authors.initials: A
authors.lastname: Apostolou
authors.forename: Howard
authors.initials: H
authors.lastname: Doong
authors.forename: Shengyun
authors.initials: S
authors.lastname: Fang
mesh_terms: D000818:Animals; D017252:CD3 Complex / Q000378:metabolism; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000201:enzymology*; D006801:Humans; D051379:Mice; D011485:Protein Binding; D013379:Substrate Specificity; D025801:Ubiquitin / Q000378:metabolism; D043743:Ubiquitin-Protein Ligase Complexes / Q000235:genetics / Q000378:metabolism*
chemical_list: D017252:CD3 Complex; C472562:CD3delta antigen; D025801:Ubiquitin; D043743:Ubiquitin-Protein Ligase Complexes