Tubby family proteins are adapters for ciliary trafficking of integral membrane proteins

Hemant B. Badgandi, Sun Hee Hwang, Issei S. Shimada, Evan Loriot, Saikat Mukhopadhyay

Research output: Contribution to journalArticle

44 Scopus citations

Abstract

The primary cilium is a paradigmatic organelle for studying compartmentalized signaling; however, unlike soluble protein trafficking, processes targeting integral membrane proteins to cilia are poorly understood. In this study, we determine that the tubby family protein TULP3 functions as a general adapter for ciliary trafficking of structurally diverse integral membrane cargo, including multiple reported and novel rhodopsin family G protein-coupled receptors (GPCRs) and the polycystic kidney disease-causing polycystin 1/2 complex. The founding tubby family member TUB also localizes to cilia similar to TULP3 and determines trafficking of a subset of these GPCRs to neuronal cilia. Using minimal ciliary localization sequences from GPCRs and fibrocystin (also implicated in polycystic kidney disease), we demonstrate these motifs to be sufficient and TULP3 dependent for ciliary trafficking. We propose a three-step model for TULP3/TUB-mediated ciliary trafficking, including the capture of diverse membrane cargo by the tubby domain in a phosphoinositide 4,5-bisphosphate (PI(4,5)P2)-dependent manner, ciliary delivery by intraflagellar transport complex A binding to the TULP3/TUB N terminus, and subsequent release into PI(4,5)P2-deficient ciliary membrane.

Original languageEnglish (US)
Pages (from-to)743-760
Number of pages18
JournalThe Journal of cell biology
Volume216
Issue number3
DOIs
StatePublished - Mar 6 2017

ASJC Scopus subject areas

  • Cell Biology

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