Phosphoinositide 3-Kinase-C2α Regulates Polycystin-2 Ciliary Entry and Protects against Kidney Cyst Formation.
Signaling from the primary cilium regulates kidney tubule development and cyst formation. However, the mechanism controlling targeting of ciliary components necessary for cilium morphogenesis and signaling is largely unknown. Here, we studied the function of class II phosphoinositide 3-kinase-C2α (PI3K-C2α) in renal tubule-derived inner medullary collecting duct 3 cells and show that PI3K-C2α resides at the recycling endosome compartment in proximity to the primary cilium base. In this subcellular location, PI3K-C2α controlled the activation of Rab8, a key mediator of cargo protein targeting to the primary cilium. Consistently, partial reduction of PI3K-C2α was sufficient to impair elongation of the cilium and the ciliary transport of polycystin-2, as well as to alter proliferation signals linked to polycystin activity. In agreement, heterozygous deletion of PI3K-C2α in mice induced cilium elongation defects in kidney tubules and predisposed animals to cyst development, either in genetic models of polycystin-1/2 reduction or in response to ischemia/reperfusion-induced renal damage. These results indicate that PI3K-C2α is required for the transport of ciliary components such as polycystin-2, and partial loss of this enzyme is sufficient to exacerbate the pathogenesis of cystic kidney disease.
Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Turin, Italy;
Irene
I
Franco
Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Turin, Italy;
Jean Piero
JP
Margaria
Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Turin, Italy;
Maria Chiara
MC
De Santis
Renal Transplantation Center "A. Vercellone", Division of Nephrology, Dialysis and Transplantation, Department of Medical Sciences, Città della Salute e della Scienza, Hospital and Research Center for Experimental Medicine (CeRMS) and Center for Molecular Biotechnology, University of Torino, Turin, Italy;
Andrea
A
Ranghino
Laboratoire de Parasitologie Moléculaire, Institut de Biologie et de Médecine Moléculaires (IBMM), Université Libre de Bruxelles, Gosselies, Charleroi, Belgium;
Daniel
D
Monteyne
Division of Genetics and Cell Biology, Dibit San Raffaele Scientific Institute, Milan, Italy;
Marco
M
Chiaravalli
Division of Genetics and Cell Biology, Dibit San Raffaele Scientific Institute, Milan, Italy;
Monika
M
Pema
Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Turin, Italy;
Carlo Cosimo
CC
Campa
Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Turin, Italy;
Edoardo
E
Ratto
Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Turin, Italy;
Federico
F
Gulluni
Laboratoire de Parasitologie Moléculaire, Institut de Biologie et de Médecine Moléculaires (IBMM), Université Libre de Bruxelles, Gosselies, Charleroi, Belgium; Center for Microscopy and Molecular Imaging (CMMI), Université Libre de Bruxelles, Gosselies, Belgium; and.
David
D
Perez-Morga
Section of Nephrology, Yale University School of Medicine, New Haven, Connecticut.
Stefan
S
Somlo
Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Turin, Italy;
Giorgio R
GR
Merlo
Division of Genetics and Cell Biology, Dibit San Raffaele Scientific Institute, Milan, Italy;
Alessandra
A
Boletta
Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Turin, Italy; emilio.hirsch@unito.it.
Emilio
E
Hirsch
D000818:Animals; D002923:Cilia / Q000502:physiology*; D058541:Class II Phosphatidylinositol 3-Kinases / Q000502:physiology*; D052177:Kidney Diseases, Cystic / Q000209:etiology; D008297:Male; D051379:Mice; D015398:Signal Transduction; D050396:TRPP Cation Channels / Q000502:physiology*
D058541:Class II Phosphatidylinositol 3-Kinases; D050396:TRPP Cation Channels
PI3K; cystic kidney; polycystins; primary cilium; proliferation; vesicular trafficking