Ciliary Targeting Motif VxPx Directs Assembly of a Trafficking Module Through Arf4

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2009 Jan 21

PMID 19153612

Citations 156

Authors

Jana Mazelova

Lisa Astuto-Gribble

Hiroki Inoue

Beatrice M Tam

Eric Schonteich

Rytis Prekeris

Orson L Moritz

Paul A Randazzo

Dusanka Deretic

Affiliations

Soon will be listed here.

Abstract

Dysfunctions of primary cilia and cilia-derived sensory organelles underlie a multitude of human disorders, including retinal degeneration, yet membrane targeting to the cilium remains poorly understood. Here, we show that the newly identified ciliary targeting VxPx motif present in rhodopsin binds the small GTPase Arf4 and regulates its association with the trans-Golgi network (TGN), which is the site of assembly and function of a ciliary targeting complex. This complex is comprised of two small GTPases, Arf4 and Rab11, the Rab11/Arf effector FIP3, and the Arf GTPase-activating protein ASAP1. ASAP1 mediates GTP hydrolysis on Arf4 and functions as an Arf4 effector that regulates budding of post-TGN carriers, along with FIP3 and Rab11. The Arf4 mutant I46D, impaired in ASAP1-mediated GTP hydrolysis, causes aberrant rhodopsin trafficking and cytoskeletal and morphological defects resulting in retinal degeneration in transgenic animals. As the VxPx motif is present in other ciliary membrane proteins, the Arf4-based targeting complex is most likely a part of conserved machinery involved in the selection and packaging of the cargo destined for delivery to the cilium.

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