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Published online
doi:10.1083/jcb.200903024
The Journal of Cell Biology, Vol. 187, No. 2, 201-217
The Rockefeller University Press, 0021-9525 $30.00
© Lim et al.
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Article

Ubiquilin and p97/VCP bind erasin, forming a complex involved in ERAD



Precious J. Lim1, Rebecca Danner1, Jing Liang1, Howard Doong1, Christine Harman1, Deepa Srinivasan1, Cara Rothenberg1, Hongmin Wang1, Yihong Ye2, Shengyun Fang1, and Mervyn J. Monteiro1

1 Medical Biotechnology Center, University of Maryland Biotechnology Institute, Baltimore, MD 21201
2 National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Bethesda, MD 20892

Correspondence to Mervyn J. Monteiro: monteiro{at}umbi.umd.edu

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.

Abbreviations used in this paper: AD, Alzheimer's disease; ERAD, ER-associated protein degradation; JAMP, JNK-associated membrane protein; UBA, ubiquitin-associated; UBL, ubiquitin-like; UPR, unfolded protein response; UBX, ubiquitin regulatory X; Y2H, yeast two-hybrid.

© 2009 Lim et al.
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