PI3K Class II α Controls Spatially Restricted Endosomal PtdIns3P and Rab11 Activation to Promote Primary Cilium Function

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

doi:10.1016/j.devcel.2014.01.022

Cited by 173 publications

(289 citation statements)

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“…For example, a module comprising MTM1/ MTMR2, PI4K2α and PIKfyve could be targeted to late endosomes via PI(3)P/ PI(3,5)P 2 , Vamp7 and Rab25, mediate PI(3)P/ PI(3,5)P 2 -to-PI(4)P conversion, allow tubule-based recycling from late endosomes and exocyst-dependent fusion with the PM (as discussed in section 4.3.1) (Rainero and Norman 2013). In ciliogenesis PI3KC2α, a known interactor of MTMR13, synthesizes a PI(3)P pool on Rab11-recycling endosomes that is required for Rab11-to-Rab8 conversion and exocyst-dependent membrane addition at the base of the primary cilium (Franco, Gulluni et al 2014). Cytokinesis, on the other hand, requires PI(3)P-as well as PI(4)P-effectors, Rab11-endosomes and exocystmediated membrane delivery to the midbody (Brill, Wong et al 2011;Schink, Raiborg et al 2013).…”

Section: Discussionmentioning

confidence: 99%

A phosphoinositide conversion mechanism for exit from endosomes

Ketel¹,

Krauß²,

Nicot³

et al. 2016

Nature

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I owe special thanks to Marnix Wieffer and Michael Krauß, who spent a lot of time helping me to get started in the lab, to overcome numerous experimental problem, I was not sure how to deal with, and frequently joined in discussions about my project with excellent advice. I am really grateful for your experimental support, Michael, and the time you invested in the project during our paper revision.Further, I would like to thank Jocelyn Laporte and his group, especially Anne-Sophie Nicot, at the IGBMC in Strasbourg for their support and a very fruitful collaboration, and Carsten Schultz and his group at the EMBL in Heidelberg for their support and constant supply with PIP/AMs. I owe special thanks to Dmytro Puchkov for the ultrastructural analysis and Eberhard Krause for mass spectrometry done within this project. I also need to acknowledge Markus Wenk and Federico Torta at the Singapore Lipidomics Incubator for joining the project at a very late stage, when we urgently needed help from lipidomics specialists. It was a pity that experiments did not work out as planned.I would further like to express my gratitude to two very skilled technicians in the AG Haucke lab: Silke Zillmann and Delia Löwe. Without your help it would have been impossible to achieve so much within the limited amount of time I had during the paper revision. by VPS34-IN1 treatment................................................... 52 2.3.11 Fluorescence microscopy................................................................................. 53 2.3.12 Flow cytometry............................................................................................ III SummaryPhosphoinositides (PIs) are a minor class of short-lived phospholipids that serve as crucial signposts of membrane identity. Thereby, PIs full fill important functions in cell signaling and membrane transport. PI 4-phosphates such as phosphatitylinositol-4-phosphate (PI(4)P) and phosphatitylinositol-4,5-bisphosphate (PI(4,5)P 2 ) are enriched at the plasma membrane (PM), on secretory organelles and lysosomes, while PI 3-phosphates, i.e.phosphatitylinositol-3-phosphate (PI(3)P), are a hallmark of the endosomal system.Directional transport between these compartments, thus, requires regulated PI conversion.However, PI conversion in exit from PI(3)P-enriched endosomes en route to the PI(4)P-and PI(4,5)P 2 -positive PM in endosomal recycling remained unknown.Here, we report that cargo exit from endosomes requires removal of PI(3)P by the PI(3)P 3-phosphatase myotubularin 1 (MTM1), and concomitant PI(4)P synthesis by PI 4-kinase type II α (PI4K2α). Loss of MTM1 causes endosomal accumulation of PI(3)P and PI(3)P effector proteins, i.e. sorting nexins, Kif16b-mediated outward traffic of PI(3)P containing endosomes and sub-plasmalemmal accumulation of exocytosis-deficient endosomes. As PI4K2α associates with MTM1 and thereby facilitates membrane recruitment of MTM1, these phenotypic changes are mimicked by loss of PI4K2α. The conversion of PI(3)P-to-PI(4)P is paralleled by a switch i...

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Section: Discussionmentioning

confidence: 99%

A phosphoinositide conversion mechanism for exit from endosomes

Ketel¹,

Krauß²,

Nicot³

et al. 2016

Nature

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165

177

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“…Although PI3P is known to be enriched at the base of the cilia in the PI3K-C2α-containing pericentriolar endosomal compartment (PRE), 25 information concerning the PIP composition of the PC has only recently started to emerge. Indeed, two recent studies 8,9 specifically addressed PIP composition within the PC.…”

Section: Phosphoinositides In the Primary Ciliummentioning

confidence: 99%

“…25,26 Although less is known about the role of PI4P, depletion of PI4P-binding protein FAPP2 (involved in the transport of newly synthesized apical proteins) led to a delay in ciliogenesis with accumulation of vesicles at the ciliary base.…”

Section: What Is Known In Terms Of Pip Functional Relevance?mentioning

confidence: 99%

“…The PI3P pool at the PRE compartment is required for Rab8 and Rab11 activation, 25 and in consequence, for ciliary elongation and cargo (eg, Smoothened and PKD2) translocation. 25,26 Although less is known about the role of PI4P, depletion of PI4P-binding protein FAPP2 (involved in the transport of newly synthesized apical proteins) led to a delay in ciliogenesis with accumulation of vesicles at the ciliary base.…”

Section: What Is Known In Terms Of Pip Functional Relevance?mentioning

confidence: 99%

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Role of Ocrl1 and Inpp5E in primary cilia assembly and maintenance: a phosphatidylinositol phosphatase relay system?

Madhivanan¹,

Ramadesika²,

Aguilar

2016

RRB

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Abstract:The primary cilium (PC) is a plasma membrane-derived structure of great importance for cell and organismal physiology. Indeed, abnormalities in assembly or function of the PC trigger the onset of a group of genetic diseases collectively known as ciliopathies. In recent years, it has become evident that the integrity and function of the PC depends substantially on signaling elements such as phosphoinositides (PI) and their regulators. Because phospholipids such as PI(4,5)P 2 constitute recruitment platforms for cytoskeleton, signaling, and trafficking machinery, control over their levels is critical for PC function. Although information about phosphoinositol phosphate (PIP) kinases in the PC is scarce, a growing body of evidence supports a role for PIP phosphatases in cilia assembly/maintenance. Indeed, deficiencies in two 5′ PIP phosphatases, Inpp5E and Ocrl1, are clearly linked to ciliopathies like Joubert/MORM syndromes, or ciliopathy-associated dise ases like Lowe syndrome. Here, we review the unique roles of these proteins and their specific site of action for ensuring ciliary integrity. Further, we discuss the possibility that a phosphatase relay system able to pass PI control from a preciliary to an intraciliary compartment is in place to ensure PC integrity/function.

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“…On the contrary, in Sh1-IMCD3 cells, only the constitutively active Rab8 Q67L could be endosomal compartment (PRE) at the base of the primary cilium where it promotes Rab11 activation upstream of Rab8. 26,27 Consistently, genetic inactivation of Pik3c2a, the murine gene encoding PI3K-C2a, leads to embryonic lethality with typical signs of ciliary dysfunction such as laterality defects and impaired Sonic hedgehog pathway activation. 26 The severity of the phenotype has precluded the analysis of ciliary dysfunction in adult organs but mouse mutants weakly expressing a truncated form of PI3K-C2a display kidney abnormalities including tubular dilations.…”

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confidence: 99%

Phosphoinositide 3-Kinase-C2α Regulates Polycystin-2 Ciliary Entry and Protects against Kidney Cyst Formation

Franco

Margaria

Santis

et al. 2016

Journal of the American Society of Nephrology

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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-C2a (PI3K-C2a) in renal tubule-derived inner medullary collecting duct 3 cells and show that PI3K-C2a resides at the recycling endosome compartment in proximity to the primary cilium base. In this subcellular location, PI3K-C2a controlled the activation of Rab8, a key mediator of cargo protein targeting to the primary cilium. Consistently, partial reduction of PI3K-C2a 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-C2a 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-C2a 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.

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PI3K Class II α Controls Spatially Restricted Endosomal PtdIns3P and Rab11 Activation to Promote Primary Cilium Function

Cited by 173 publications

References 47 publications

A phosphoinositide conversion mechanism for exit from endosomes

A phosphoinositide conversion mechanism for exit from endosomes

Role of Ocrl1 and Inpp5E in primary cilia assembly and maintenance: a phosphatidylinositol phosphatase relay system?

Phosphoinositide 3-Kinase-C2α Regulates Polycystin-2 Ciliary Entry and Protects against Kidney Cyst Formation

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