Clearance of Rhodopsin(P23H) aggregates requires the ERAD effector VCP.
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.
Griciuc
Ana
A
Department of Protein Science, Helmholtz Zentrum Muenchen-German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany.
Aron
Liviu
L
Piccoli
Giovanni
G
Ueffing
Marius
M
D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017510:Protein Folding; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000166:cytology; D012174:Retinitis Pigmentosa / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012243:Rhodopsin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000074405:Valosin Containing Protein
D018797:Cell Cycle Proteins; D018832:Molecular Chaperones; D011993:Recombinant Fusion Proteins; D012243:Rhodopsin; D046988:Proteasome Endopeptidase Complex; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein; C000614179:Vcp protein, mouse