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

Biochimica Et Biophysica Acta
Ana GriciucMarius Ueffing

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.

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Citations

Nov 22, 2011·Journal of Molecular Histology·Huseyin OrtakHelin Deniz Demir
Aug 3, 2012·Molecular Biology of the Cell·Dimitra AthanasiouMichael E Cheetham
Jun 8, 2012·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Christine InsinnaEdward N Pugh
Jul 25, 2014·Human Molecular Genetics·Dimitra AthanasiouMichael E Cheetham
May 21, 2013·FEBS Letters·Dimitra AthanasiouMichael E Cheetham
May 31, 2011·Trends in Molecular Medicine·Ana GriciucMarius Ueffing
Apr 28, 2016·Biochimica Et Biophysica Acta·Megan GraggP S-H Park
Oct 17, 2017·Human Molecular Genetics·Dimitra AthanasiouMichael E Cheetham
Jan 24, 2019·Cold Spring Harbor Perspectives in Biology·Patrick G NeedhamJeffrey L Brodsky
May 7, 2016·Human Molecular Genetics·Antonella ComitatoValeria Marigo
Jun 4, 2021·Bioconjugate Chemistry·Marco BassettoOlivier Zelphati

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