Ubiquilin and p97/VCP bind erasin, forming a complex involved in ERAD.
Unwanted proteins in the endoplasmic reticulum (ER) are exported into the cytoplasm and degraded by the proteasome through the ER-associated protein degradation pathway (ERAD). Disturbances in ERAD are linked to ER stress, which has been implicated in the pathogenesis of several human diseases. However, the composition and organization of ERAD complexes in human cells is still poorly understood. In this paper, we describe a trimeric complex that we propose functions in ERAD. Knockdown of erasin, a platform for p97/VCP and ubiquilin binding, or knockdown of ubiquilin in human cells slowed degradation of two classical ERAD substrates. In Caenorhabditis elegans, ubiquilin and erasin are ER stress-response genes that are regulated by the ire-1 branch of the unfolded protein response pathway. Loss of ubiquilin or erasin resulted in activation of ER stress, increased accumulation of polyubiquitinated proteins, and shortened lifespan in worms. Our results strongly support a role for this complex in ERAD and in the regulation of ER stress.
Lim
Precious J
PJ
Medical Biotechnology Center, University of Maryland Biotechnology Institute, Baltimore, MD 21201, USA.
Danner
Rebecca
R
Liang
Jing
J
Doong
Howard
H
Harman
Christine
C
Srinivasan
Deepa
D
Rothenberg
Cara
C
Wang
Hongmin
H
Ye
Yihong
Y
Fang
Shengyun
S
Monteiro
Mervyn J
MJ
D048868:Adaptor Proteins, Signal Transducing; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000071183:Autophagy-Related Proteins; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011485:Protein Binding; D017510:Protein Folding; D034622:RNA Interference; D013312:Stress, Physiological; D013379:Substrate Specificity; D000074405:Valosin Containing Protein
D048868:Adaptor Proteins, Signal Transducing; D000071183:Autophagy-Related Proteins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D008565:Membrane Proteins; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; C107792:UBQLN1 protein, human; C515819:UBXN4 protein, human; D046988:Proteasome Endopeptidase Complex; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein