Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 280, Issue 41, Pages 34530-34537Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M508890200
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- NIDDK NIH HHS [R01 DK049194, DK49194, R01 DK056294, R29 DK049194, DK56294] Funding Source: Medline
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Inositol 1,4,5-trisphosphate (IP3) receptors form tetrameric, IP3-gated channels in endoplasmic reticulum membranes that govern the release of Ca2+ from this organelle. In response to activation of certain G protein-coupled receptors that persistently elevate IP3 concentration, IP3 receptors are ubiquitinated and degraded by the ubiquitin-proteasome pathway. IP3 receptor ubiquitination is mediated by the ubiquitin-conjugating enzyme, (mam)Ubc7, a component of the endoplasmic reticulum-associated degradation pathway. However, the mechanism by which ubiquitinated IP3 receptors are transferred to the proteasome is not known. Here, we examine this process and show in several mammalian cell types that the ATPase p97 associates with IP3 receptors in response to hormonal stimuli that induce IP3 receptor ubiquitination. To examine the functional relevance of the p97 interaction with IP3 receptors, we stably and specifically reduced p97 protein levels by 62 +/- 3% in Rat-1 fibroblasts using RNA interference. In these cells, endothelin-1- induced IP3 receptor degradation was markedly retarded and the accumulation of ubiquitinated IP3 receptors was markedly enhanced. These effects were reversed by expression of exogenous p97. In addition, Ufd1 and Npl4, which complex with p97, also associated with IP3 receptors upon hormonal stimulation. We conclude that the p97-Ufd1-Npl4 complex couples ubiquitinated IP3 receptors to proteasomal degradation and, thus, plays a key role in IP3 receptor processing. These data also establish that the p97-Ufd1-Npl4 complex mediates endoplasmic reticulum-associated degradation in mammalian cells.
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