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Journal Article

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


Aron,  L.
Department: Molecular Neurobiology / Klein, MPI of Neurobiology, Max Planck Society;

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Griciuc, A., Aron, L., Piccoli, G., & Ueffing, M. (2010). Clearance of Rhodopsin(P23H) aggregates requires the ERAD effector VCP. Biochimica et Biophysica Acta-Molecular Cell Research, 1803(3), 424-434.

Cite as: https://hdl.handle.net/11858/00-001M-0000-0012-1FEC-F
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. (C) 2010 Elsevier B.V. All rights reserved.