Multiple ciliary localization signals control INPP5E ciliary targeting.

Journal Article (Journal Article)

Primary cilia are sensory membrane protrusions whose dysfunction causes ciliopathies. INPP5E is a ciliary phosphoinositide phosphatase mutated in ciliopathies like Joubert syndrome. INPP5E regulates numerous ciliary functions, but how it accumulates in cilia remains poorly understood. Herein, we show INPP5E ciliary targeting requires its folded catalytic domain and is controlled by four conserved ciliary localization signals (CLSs): LLxPIR motif (CLS1), W383 (CLS2), FDRxLYL motif (CLS3) and CaaX box (CLS4). We answer two long-standing questions in the field. First, partial CLS1-CLS4 redundancy explains why CLS4 is dispensable for ciliary targeting. Second, the essential need for CLS2 clarifies why CLS3-CLS4 are together insufficient for ciliary accumulation. Furthermore, we reveal that some Joubert syndrome mutations perturb INPP5E ciliary targeting, and clarify how each CLS works: (i) CLS4 recruits PDE6D, RPGR and ARL13B, (ii) CLS2-CLS3 regulate association to TULP3, ARL13B, and CEP164, and (iii) CLS1 and CLS4 cooperate in ATG16L1 binding. Altogether, we shed light on the mechanisms of INPP5E ciliary targeting, revealing a complexity without known parallels among ciliary cargoes.

Full Text

Duke Authors

Cited Authors

  • Cilleros-Rodriguez, D; Martin-Morales, R; Barbeito, P; Deb Roy, A; Loukil, A; Sierra-Rodero, B; Herranz, G; Pampliega, O; Redrejo-Rodriguez, M; Goetz, SC; Izquierdo, M; Inoue, T; Garcia-Gonzalo, FR

Published Date

  • September 5, 2022

Published In

Volume / Issue

  • 11 /

PubMed ID

  • 36063381

Pubmed Central ID

  • PMC9444247

Electronic International Standard Serial Number (EISSN)

  • 2050-084X

Digital Object Identifier (DOI)

  • 10.7554/eLife.78383


  • eng

Conference Location

  • England