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

Irene Franco; Federico Gulluni; Carlo C. Campa; Carlotta Costa; JeanPiero Margaria; Elisa Ciraolo; Miriam Martini; Daniel Monteyne; Elisa De Luca; Giulia Germena; York Posor; Tania Maffucci; Stefano Marengo; Volker Haucke; Marco Falasca; David Perez-Morga; Alessandra Boletta; Giorgio R. Merlo; Emilio Hirsch

doi:10.1016/j.devcel.2014.01.022

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

Irene Franco, Federico Gulluni, Carlo C. Campa, Carlotta Costa, JeanPiero Margaria, Elisa Ciraolo, Miriam Martini, Daniel Monteyne, Elisa De Luca, Giulia Germena, York Posor, Tania Maffucci, Stefano Marengo, Volker Haucke, Marco Falasca, David Perez-Morga, Alessandra Boletta, Giorgio R. Merlo, Emilio Hirsch

IRCCS Ospedale San Raffaele

Research output: Contribution to journal › Article › peer-review

Abstract

Multiple phosphatidylinositol (PtdIns) 3-kinases (PI3Ks) can produce PtdIns3. P 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 PtdIns3. P. Loss of PI3K-C2α-derived PtdIns3. P 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 PtdIns3. P levels in cells lacking PI3K-C2α rescues Rab11 activation, primary cilium length, and Shh pathway induction. Thus, PI3K-C2α regulates the formation of a PtdIns3. P pool at the PRE required for Rab11 and Shh pathway activation.

Original language	English
Pages (from-to)	647-658
Number of pages	12
Journal	Developmental Cell
Volume	28
Issue number	6
DOIs	https://doi.org/10.1016/j.devcel.2014.01.022
Publication status	Published - Mar 31 2014

ASJC Scopus subject areas

Developmental Biology
Medicine(all)

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Franco, I., Gulluni, F., Campa, C. C., Costa, C., Margaria, J., 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, G. R., & Hirsch, E. (2014). PI3K class II α controls spatially restricted endosomal PtdIns3P and Rab11 activation to promote primary cilium function. Developmental Cell, 28(6), 647-658. https://doi.org/10.1016/j.devcel.2014.01.022

PI3K class II α controls spatially restricted endosomal PtdIns3P and Rab11 activation to promote primary cilium function. / Franco, Irene; Gulluni, Federico; Campa, Carlo C.; Costa, Carlotta; Margaria, JeanPiero; Ciraolo, Elisa; Martini, Miriam; Monteyne, Daniel; De Luca, Elisa; Germena, Giulia; Posor, York; Maffucci, Tania; Marengo, Stefano; Haucke, Volker; Falasca, Marco; Perez-Morga, David; Boletta, Alessandra; Merlo, Giorgio R.; Hirsch, Emilio.

In: Developmental Cell, Vol. 28, No. 6, 31.03.2014, p. 647-658.

Research output: Contribution to journal › Article › peer-review

Franco, I, Gulluni, F, Campa, CC, Costa, C, Margaria, J, 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 2014, 'PI3K class II α controls spatially restricted endosomal PtdIns3P and Rab11 activation to promote primary cilium function', Developmental Cell, vol. 28, no. 6, pp. 647-658. https://doi.org/10.1016/j.devcel.2014.01.022

Franco, Irene ; Gulluni, Federico ; Campa, Carlo C. ; Costa, Carlotta ; Margaria, JeanPiero ; Ciraolo, Elisa ; Martini, Miriam ; Monteyne, Daniel ; De Luca, Elisa ; Germena, Giulia ; Posor, York ; Maffucci, Tania ; Marengo, Stefano ; Haucke, Volker ; Falasca, Marco ; Perez-Morga, David ; Boletta, Alessandra ; Merlo, Giorgio R. ; Hirsch, Emilio. / PI3K class II α controls spatially restricted endosomal PtdIns3P and Rab11 activation to promote primary cilium function. In: Developmental Cell. 2014 ; Vol. 28, No. 6. pp. 647-658.

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abstract = "Multiple phosphatidylinositol (PtdIns) 3-kinases (PI3Ks) can produce PtdIns3. P 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 PtdIns3. P. Loss of PI3K-C2α-derived PtdIns3. P 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 PtdIns3. P levels in cells lacking PI3K-C2α rescues Rab11 activation, primary cilium length, and Shh pathway induction. Thus, PI3K-C2α regulates the formation of a PtdIns3. P pool at the PRE required for Rab11 and Shh pathway activation.",

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AU - Margaria, JeanPiero

AU - Ciraolo, Elisa

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AU - Monteyne, Daniel

AU - De Luca, Elisa

AU - Germena, Giulia

AU - Posor, York

AU - Maffucci, Tania

AU - Marengo, Stefano

AU - Haucke, Volker

AU - Falasca, Marco

AU - Perez-Morga, David

AU - Boletta, Alessandra

AU - Merlo, Giorgio R.

AU - Hirsch, Emilio

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N2 - Multiple phosphatidylinositol (PtdIns) 3-kinases (PI3Ks) can produce PtdIns3. P 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 PtdIns3. P. Loss of PI3K-C2α-derived PtdIns3. P 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 PtdIns3. P levels in cells lacking PI3K-C2α rescues Rab11 activation, primary cilium length, and Shh pathway induction. Thus, PI3K-C2α regulates the formation of a PtdIns3. P pool at the PRE required for Rab11 and Shh pathway activation.

AB - Multiple phosphatidylinositol (PtdIns) 3-kinases (PI3Ks) can produce PtdIns3. P 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 PtdIns3. P. Loss of PI3K-C2α-derived PtdIns3. P 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 PtdIns3. P levels in cells lacking PI3K-C2α rescues Rab11 activation, primary cilium length, and Shh pathway induction. Thus, PI3K-C2α regulates the formation of a PtdIns3. P pool at the PRE required for Rab11 and Shh pathway activation.

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