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PMID: 24697898 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

PI3K class II α controls spatially restricted endosomal PtdIns3P and Rab11 activation to promote primary cilium function.

Developmental cell ·Vol. 28 ·No. 6 ·2014-03-31 ·Pages 647-58

Franco I, Gulluni F, Campa CC, Costa C, Margaria JP, Ciraolo E, Martini M, Monteyne D, De Luca E, Germena G, Posor Y, Maffucci T, Marengo S, Haucke V, Falasca M, Perez-Morga D, Boletta A, Merlo GR, Hirsch E

Abstract

Multiple phosphatidylinositol (PtdIns) 3-kinases (PI3Ks) can produce PtdIns3P to control endocytic trafficking, but whether enzyme specialization occurs in defined subcellular locations is unclear. Here, we report that PI3K-C2α is enriched in the pericentriolar recycling endocytic compartment (PRE) at the base of the primary cilium, where it regulates production of a specific pool of PtdIns3P. Loss of PI3K-C2α-derived PtdIns3P leads to mislocalization of PRE markers such as TfR and Rab11, reduces Rab11 activation, and blocks accumulation of Rab8 at the primary cilium. These changes in turn cause defects in primary cilium elongation, Smo ciliary translocation, and Sonic Hedgehog (Shh) signaling and ultimately impair embryonic development. Selective reconstitution of PtdIns3P levels in cells lacking PI3K-C2α rescues Rab11 activation, primary cilium length, and Shh pathway induction. Thus, PI3K-C2α regulates the formation of a PtdIns3P pool at the PRE required for Rab11 and Shh pathway activation.

MeSH Terms
Animals Cell Movement/physiology Cells, Cultured Cilia/physiology Embryo, Mammalian/cytology,metabolism Endosomes/metabolism Female Fibroblasts/cytology,metabolism Immunoblotting Immunoprecipitation Male Mice Mice, Inbred C57BL Mice, Knockout Phosphatidylinositol 3-Kinases/physiology Phosphatidylinositol Phosphates/metabolism Phosphoinositide-3 Kinase Inhibitors Protein Transport RNA, Small Interfering/genetics Receptors, G-Protein-Coupled/metabolism Receptors, Transferrin/metabolism Signal Transduction Smoothened Receptor rab GTP-Binding Proteins/metabolism
Chemicals
Phosphatidylinositol Phosphates Phosphoinositide-3 Kinase Inhibitors RNA, Small Interfering Receptors, G-Protein-Coupled Receptors, Transferrin Smo protein, mouse Smoothened Receptor Tfrc protein, mouse phosphatidylinositol 3-phosphate Pik3c2a protein, mouse rab11 protein rab GTP-Binding Proteins
Authors & Affiliations
19 authors, click to expand affiliations / ORCID
Franco Irene
Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy.
Gulluni Federico
Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy.
Campa Carlo C
Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy.
Costa Carlotta
Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy.
Margaria Jean Piero
Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy.
Ciraolo Elisa
Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy.
Martini Miriam
Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy.
Monteyne Daniel
Laboratoire de Parasitologie Moléculaire, Institut de Biologie et de Médecine Moléculaires (IBMM), Université Libre de Bruxelles, Gosselies, 6041 Charleroi, Belgium.
De Luca Elisa
Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy.
Germena Giulia
Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy.
Posor York
Leibniz Institut für Molekulare Pharmakologie, 13125 Berlin, Germany.
Maffucci Tania
Centre for Diabetes, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
Marengo Stefano
Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy.
Haucke Volker
Leibniz Institut für Molekulare Pharmakologie, 13125 Berlin, Germany.
Falasca Marco
Centre for Diabetes, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
Perez-Morga David
Laboratoire de Parasitologie Moléculaire, Institut de Biologie et de Médecine Moléculaires (IBMM), Université Libre de Bruxelles, Gosselies, 6041 Charleroi, Belgium; Center for Microscopy and Molecular Imaging-CMMI, Université Libre de Bruxelles, 8 rue Adrienne Bolland, 6041 Gosselies, Belgium.
Boletta Alessandra
Division of Genetics and Cell Biology, Dibit San Raffaele Scientific Institute, 20132 Milan, Italy.
Merlo Giorgio R
Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy.
Hirsch Emilio
Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy. Electronic address: [email protected].
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Article Info
Journal
Developmental cell
Abbr.
Dev Cell
ISSN
1878-1551
DOI
10.1016/j.devcel.2014.01.022
Email
[email protected]
Published
2014-03-31
Pages
647-58
Language
English
Region
United States
NLM ID
101120028
PMCID
PMC4042153
Subset
IM
Grants
Telethon · GGP12183 · Italy
External Links
PubMed source DOI: 10.1016/j.devcel.2014.01.022 PMC Full Text View journal details
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