Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 102, Issue 9, Pages 3301-3306Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0500095102
Keywords
ADP-ribosylation factor GTPase; membrane trafficking; retinitis pigmetosa; rhodopsin
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Funding
- NEI NIH HHS [R01 EY006225, EY-6225, R01 EY012421, EY-12421] Funding Source: Medline
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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.
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