A conserved signal and GTPase complex are required for the ciliary transport of polycystin-1

Heather H. Ward, Ursa Brown-Glaberman, Jing Wang, Yoshiko Morita, Seth L. Alper, Edward J. Bedrick, Vincent H. Gattone, Dusanka Deretic, Angela Wandinger-Ness

Research output: Contribution to journalArticlepeer-review

75 Scopus citations

Abstract

Primary cilia regulate epithelial differentiation and organ function. Failure of mutant polycystins to localize to cilia abolishes flow-stimulated calcium signaling and causes autosomal dominant polycystic kidney disease. We identify a conserved amino acid sequence, KVHPSST, in the C-terminus of polycystin-1 (PC1) that serves as a ciliary-targeting signal. PC1 binds a multimeric protein complex consisting of several GTPases (Arf4, Rab6, Rab11) and the GTPase-activating protein (GAP), ArfGAP with SH3 domain, ankyrin repeat and PH domain 1 (ASAP1) in the Golgi, which facilitates vesicle budding and Golgi exocytosis. A related N-terminal ciliary-targeting sequence in polycystin-2 similarly binds Arf4. Deletion of the extreme C-terminus of PC1 ablates Arf4 and ASAP1 binding and prevents ciliary localization of an integral membrane CD16.7-PC1 chimera. Interactions are confirmed for chimeric and endogenous proteins through quantitated in vitro and cell-based approaches. PC1 also complexes with Rab8; knockdown of trafficking regulators Arf4 or Rab8 functionally blocks CD16.7-PC1 trafficking to cilia. Mutations in rhodopsin disrupt a similar signal and cause retinitis pigmentosa, while Bardet-Biedl syndrome, primary open-angle glaucoma, and tumor cell invasiveness are linked to dysregulation of ASAP1 or Rab8 or its effectors. In this paper, we provide evidence for a conserved GTPase-dependent ciliary-trafficking mechanism that is shared between epithelia and neurons, and is essential in ciliary-trafficking and cell homeostasis.

Original languageEnglish (US)
Pages (from-to)3289-3305
Number of pages17
JournalMolecular biology of the cell
Volume22
Issue number18
DOIs
StatePublished - Sep 15 2011
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Fingerprint

Dive into the research topics of 'A conserved signal and GTPase complex are required for the ciliary transport of polycystin-1'. Together they form a unique fingerprint.

Cite this