Research Output per year
Endoplasmic reticulum-associated degradation (ERAD) represents a principle quality control (QC) mechanism to clear misfolded proteins in the ER; however, its physiological significance and the nature of endogenous ERAD substrates remain largely unknown. Here we discover that IRE1alpha, the sensor of unfolded protein response (UPR), is a bona fide substrate of the Sel1L-Hrd1 ERAD complex. Mechanistically, ERAD-mediated IRE1alpha degradation occurs in a Bip-dependent manner under basal conditions and is attenuated in response to ER stress. Both intramembrane hydrophilic residues of IRE1alpha and lectin protein OS9 are required for IRE1alpha degradation. ERAD deficiency causes IRE1alpha protein stabilization, accumulation and mild activation both in vitro and in vivo, leading to cellular hypersensitivity to ER stress and inflammation. Furthermore, though enterocyte-specific Sel1L-knockout mice (Sel1LΔIEC) are viable and appear normal, they are more susceptible to experimental colitis in an IRE1alpha-dependent but CHOP-independent manner. Collectively, these results demonstrate that Sel1L-Hrd1 ERAD serves a distinct, essential function in restraint of IRE1alpha signaling in vivo by managing its protein turnover.
|Date made available||4 Nov 2015|
Kersten, S., 2015, In : Nature Cell Biology. 17, 12, p. 1546-1555
Research output: Contribution to journal › Article › Academic › peer-review
Sun, S. (Creator), Shi, G. (Creator), Sha, H. (Creator), Ji, Y. (Creator), Han, X. (Creator), Shu, X. (Creator), Ma, H. (Creator), Takamasa, I. (Creator), Gao, B. (Creator), Bu, P. (Creator), Guber, R. D. (Creator), Shen, X. (Creator), Lee, A. H. (Creator), Iwawaki, T. (Creator), Paton, A. W. (Creator), Paton, J. C. (Creator), Fang, D. (Creator), Tsai, B. (Creator), Yates III, J. R. (Creator), Wu, H. (Creator), Kersten, S. (Creator), Long, Q. (Creator), Duhamel, G. E. (Creator), Simpson, K. W. (Creator), Qi, L. (Creator) (4 Nov 2015). IRE1alpha is an endogenous substrate of endoplasmic reticulum-associated degradation. Wageningen University.