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Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
Clearance of Rhodopsin(P23H) aggregates requires the ERAD effector VCP.
Biochim. Biophys. Acta-Mol. Cell Res. 1803, 424-434 (2010)
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.
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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
ATPase; ERAD; Proteasome; Rhodopsin; Retinitis pigmentosa; VCP
ISSN (print) / ISBN
0167-4889
e-ISSN
1879-2596
Quellenangaben
Band: 1803,
Heft: 3,
Seiten: 424-434
Verlag
Elsevier
Nichtpatentliteratur
Publikationen
Begutachtungsstatus
Peer reviewed
Institut(e)
CF Metabolomics & Proteomics (CF-MPC)