Rhodopsin C terminus, the site of mutations causing retinal disease, regulates trafficking by binding to ADP-ribosylation factor 4 (ARF4).
The maintenance of photoreceptor cell polarity is compromised by the rhodopsin mutations causing the human disease autosomal dominant retinitis pigmentosa. The severe form mutations occur in the C-terminal sorting signal of rhodopsin, VXPX-COOH. Here, we report that this sorting motif binds specifically to the small GTPase ARF4, a member of the ARF family of membrane budding and protein sorting regulators. The effects of blocking ARF4 action were functionally equivalent to the effects of blocking the rhodopsin C-terminal sorting signal. ARF4 was essential for the generation of post-Golgi carriers targeted to the rod outer segments of retinal photoreceptors. Thus, the severe retinitis pigmentosa alleles that affect the rhodopsin sorting signal interfere with interactions between ARF4 and rhodopsin, leading to aberrant trafficking and initiation of retinal degeneration.
Deretic
Dusanka
D
Department of Surgery, Division of Ophthalmology, and Cell Biology and Physiology, University of New Mexico, Albuquerque, NM 87131, USA. dderetic@salud.unm.edu
Williams
Andrew H
AH
Ransom
Nancy
N
Morel
Valerie
V
Hargrave
Paul A
PA
Arendt
Anatol
A
D020727:ADP-Ribosylation Factors / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D004591:Electrophoresis, Polyacrylamide Gel; D006056:Golgi Apparatus / Q000378:metabolism; D018613:Microscopy, Confocal; D009154:Mutation; D011485:Protein Binding; D021381:Protein Transport; D011898:Ranidae; D017382:Reactive Oxygen Species; D012243:Rhodopsin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D017382:Reactive Oxygen Species; D012243:Rhodopsin; D020727:ADP-Ribosylation Factors
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