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Biochim Biophys Acta. 2010 Mar;1803(3):424-34. doi: 10.1016/j.bbamcr.2010.01.008. Epub 2010 Jan 25.

Clearance of Rhodopsin(P23H) aggregates requires the ERAD effector VCP.

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1
Department of Protein Science, Helmholtz Zentrum Muenchen-German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany.

Abstract

Dominant mutations in the visual pigment Rhodopsin (Rh) cause retinitis pigmentosa (RP) characterized by progressive blindness and retinal degeneration. The most common Rh mutation, Rh(P23H) forms aggregates in the endoplasmic reticulum (ER) and impairs the proteasome; however, the mechanisms linking Rh aggregate formation to proteasome dysfunction and photoreceptor cell loss remain unclear. Using mammalian cell cultures, we provide the first evidence that misfolded Rh(P23H) is a substrate of the ERAD effector VCP, an ATP-dependent chaperone that extracts misfolded proteins from the ER and escorts them for proteasomal degradation. VCP co-localizes with misfolded Rh(P23H) in retinal cells and requires functional N-terminal and D1 ATPase domains to form a complex with Rh(P23H) aggregates. Furthermore, VCP uses its D2 ATPase activity to promote Rh(P23H) aggregate retrotranslocation and proteasomal delivery. Our results raise the possibility that modulation of VCP and ERAD activity might have potential therapeutic significance for RP.

PMID:
20097236
DOI:
10.1016/j.bbamcr.2010.01.008
[Indexed for MEDLINE]
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