Phosphatidylinositol 5‐phosphate: A nuclear stress lipid and a tuner of membranes and cytoskeleton dynamics

Viaud, Julien; Boal, Frédéric; Tronchère, Hélène; Gaits‐Iacovoni, Frédérique; Payrastre, Bernard

doi:10.1002/bies.201300132

Cited by 39 publications

(40 citation statements)

References 104 publications

(185 reference statements)

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“…However, PI5P effectors outside the nucleus that might be involved in its function on membranes facing the cytosol are sparse. Very recently, our laboratory has shown that PI5P is able to activate the small GTPase Rac1, therefore regulating actin cytoskeleton dynamics and cell invasion (Viaud et al, 2014b). Our present work identifies TOM1, through its VHS domain, as a PI5P effector regulating endosomal maturation.…”

Section: Discussionmentioning

confidence: 55%

“…In the nucleus, in response to stress signaling (Jones et al, 2006), PI5P acts as a regulator of chromatin organization and gene expression though its interaction with the PHD (plant homeodomain) domaincontaining protein ING2 (Gozani et al, 2003). Outside the nucleus, PI5P has been shown to be implicated in the regulation of membrane dynamics and trafficking (Shisheva, 2013;Viaud et al, 2014a). In this context, three potential pathways lead to an increase in the amount of PI5P: one involves the direct phosphorylation of phosphatidylinositol by the 5-kinase PIKfyve, the second involves a PI3P-PI(3,5)P 2 -PI5P route with the concerted action of the PIKfyve and the 3-phosphatases of the myotubularin family (Viaud et al, 2014a) and the third uses PI(4,5)P 2 as a source of PI5P.…”

Section: Introductionmentioning

confidence: 99%

“…Outside the nucleus, PI5P has been shown to be implicated in the regulation of membrane dynamics and trafficking (Shisheva, 2013;Viaud et al, 2014a). In this context, three potential pathways lead to an increase in the amount of PI5P: one involves the direct phosphorylation of phosphatidylinositol by the 5-kinase PIKfyve, the second involves a PI3P-PI(3,5)P 2 -PI5P route with the concerted action of the PIKfyve and the 3-phosphatases of the myotubularin family (Viaud et al, 2014a) and the third uses PI(4,5)P 2 as a source of PI5P. This latter pathway was originally described in cells infected with the bacterium Shigella flexneri, through the injection of the virulence factor IpgD, a PI(4,5)P 2 4-phosphatase (Niebuhr et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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TOM1 is a PI5P effector involved in the regulation of endosomal maturation

Boal

Mansour

Gayral

et al. 2015

Journal of Cell Science

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Phosphoinositides represent a major class of lipids specifically involved in the organization of signaling cascades, maintenance of the identity of organelles and regulation of multiple intracellular trafficking steps. We previously reported that phosphatidylinositol 5-monophosphate (PI5P), produced by the Shigella flexneri phosphatase IpgD, is implicated in the endosomal sorting of the epidermal growth factor receptor (EGFR). Here, we show that the adaptor protein TOM1 is a new direct binding partner of PI5P. We identify the domain of TOM1 involved in this interaction and characterize the binding motif. Finally, we demonstrate that the recruitment of TOM1 by PI5P on signaling endosomes is responsible for the delay in EGFR degradation and fluid-phase bulk endocytosis. Taken together, our data strongly suggest that PI5P enrichment in signaling endosomes prevents endosomal maturation through the recruitment of TOM1, and point to a new function of PI5P in regulating discrete maturation steps in the endosomal system.

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Section: Discussionmentioning

confidence: 55%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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TOM1 is a PI5P effector involved in the regulation of endosomal maturation

Boal

Mansour

Gayral

et al. 2015

Journal of Cell Science

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“…T he phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are an enigmatic family of three (PI5P4Kα, -β, and -γ) with cellular functions that remain poorly understood (1)(2)(3). In general, their principal activity is believed to be to remove and thus, regulate the levels of their substrate phosphatidylinositol 5-phosphate (PI5P).…”

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confidence: 99%

In B cells, phosphatidylinositol 5-phosphate 4-kinase–α synthesizes PI(4,5)P₂to impact mTORC2 and Akt signaling

Bulley

Droubi

Clarke

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are enigmatic lipid kinases with physiological functions that are incompletely understood, not the least because genetic deletion and cell transfection have led to contradictory data. Here, we used the genetic tractability of DT40 cells to create cell lines in which endogenous PI5P4Kα was removed, either stably by genetic deletion or transiently (within 1 h) by tagging the endogenous protein genomically with the auxin degron. In both cases, removal impacted Akt phosphorylation, and by leaving one PI5P4Kα allele present but mutating it to be kinase-dead or have PI4P 5-kinase activity, we show that all of the effects on Akt phosphorylation were dependent on the ability of PI5P4Kα to synthesize phosphatidylinositol (4,5)-bisphosphate [PI(4,5) P 2 ] rather than to remove PI5P. Although stable removal of PI5P4Kα resulted in a pronounced decrease in Akt phosphorylation at Thr308 and Ser473, in part because of reduced plasma membrane PIP 3 , its acute removal led to an increase in Akt phosphorylation only at Ser473. This process invokes activation primarily of mammalian target of rapamycin complex 2 (mTORC2), which was confirmed by increased phosphorylation of other mTORC2 substrates. These findings establish PI5P4Kα as a kinase that synthesizes a physiologically relevant pool of PI(4,5)P 2 and as a regulator of mTORC2, and show a phenomenon similar to the "butterfly effect" described for phosphatidylinositol 3-kinase Iα [Hart JR, et al. (2015) Proc Natl Acad Sci USA 112(4):1131-1136], whereby through apparently the same underlying mechanism, the removal of a protein's activity from a cell can have widely divergent effects depending on the time course of that removal.phosphatidylinositol 5-phosphate 4-kinase | phosphatidylinositol 5-phosphate | phosphatidylinositol (4,5)-bisphosphate | Akt | mTOR T he phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are an enigmatic family of three (PI5P4Kα, -β, and -γ) with cellular functions that remain poorly understood (1-3). In general, their principal activity is believed to be to remove and thus, regulate the levels of their substrate phosphatidylinositol 5-phosphate (PI5P). Phenotypes from knockout mice have highlighted that PI5P4Ks have important roles to play in physiology and pathology, including links between PI5P4Ks and the Akt signaling pathway, and other studies have pointed to roles in the generation of cancer (3). A number of key questions, however, remain unanswered. Knocking proteins out or down (by RNAi) is a long-term strategy that may lead to indirect changes, such as, for example, those highlighted in the recent study by Hart et al. (4) concerning the indirect long-term consequences of a point mutation in phosphatidylinositol 3-kinase-α (PI3Kα). Another issue still unresolved for PI5P4Ks is whether removal of PI5P is their only function or whether their ability to synthesize phosphatidylinositol (4,5)-bisphosphate [PI(4,5)P 2 ] may also be important (5, 6).We have recently used the high homologous recombi...

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“…Le PtdIns5P est l'un des derniers PI à avoir été identifié [9]. Il est présent en faible quantité dans les cellules quiescentes.…”

Section: Ptdins5punclassified

Les phosphoinositides

Viaud

Payrastre

2015

Med Sci (Paris)

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> En interagissant spécifiquement avec des protéines, les phosphoinositides organisent de manière spatio-temporelle la formation de complexes protéiques impliqués dans le contrôle de la signalisation intracellulaire, du trafic vésiculaire ou de l'assemblage du cytosquelette. Un ensemble de kinases et de phosphatases spécifiques assure la production, la dégradation et l'interconversion des phosphoinositides, ce qui permet d'atteindre un haut niveau de précision dans la régulation de la dynamique cellulaire coordonnée par ces lipides. L'implication directe de ces enzymes dans des maladies génétiques, des cancers ou des pathologies infectieuses, ainsi que l'arrivée récente d'inhibiteurs ciblant certaines phosphoinositides kinases en clinique, soulignent l'importance de ces lipides et de leur métabolisme dans le domaine biomédical. < phosphorylation du noyau inositol ( Figure 1B . Sous l'effet de divers stimulus (hormones, facteurs de croissance, molécules adhésives, chimio-attractants, stress, etc.), la relocalisation et la régulation des PI-kinases et -phosphatases permettent de générer de façon rapide et plus ou moins transitoire des territoires membranaires enrichis ou appauvris en certains PI. Ces PI peuvent ainsi orienter et coordonner le recrutement de certaines protéines au niveau des membranes cellulaires où ils sont produits, pour réguler la dynamique cellulaire. Ces dernières années, l'utilisation des domaines protéiques d'interaction avec les PI pour localiser ces lipides par des approches de biologie cellulaire a suscité beaucoup d'intérêt. Il a ainsi été montré que si le PtdIns(4,5)P 2 et le PtdIns(3,4,5)P 3 sont majoritairement localisés dans la membrane plasmique [1,2] Les phosphoinositides (PI), appelés parfois lipides à inositol, sont des glycérophospholipides qui repré-sentent environ 10 à 15 % des phospholipides membranaires. Les deux acides gras qui les constituent majoritairement sont l'acide stéarique (C18:0) 1 en position 1 et l'acide arachidonique (C20:4) en position 2, mais d'autres espèces moléculaires minoritaires coexistent dans la plupart des cellules. Ces acides gras sont fixés sur le squelette glycérol, lui-même relié au noyau inositol par une liaison phosphodiester ( Figure 1A). Malgré la présence de 5 groupements hydroxyle libres sur le noyau inositol, seules les positions 3, 4 et 5 ont été retrouvées phosphorylées par des kinases spécifiques. Des problèmes d'encombrement stérique empêchent vraisemblablement l'accès des positions 1 et 6 aux kinases. Ainsi, en plus du phosphatidylinositol (PtdIns) qui représente 80 % du total des PI, 7 autres PI ont été identifiés, correspondant aux diverses combinaisons de 1 D'après la nomenclature, C18:0 signifie que l'acide gras possède 18 atomes de carbone et ne présente pas d'insaturation.

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Phosphatidylinositol 5‐phosphate: A nuclear stress lipid and a tuner of membranes and cytoskeleton dynamics

Cited by 39 publications

References 104 publications

TOM1 is a PI5P effector involved in the regulation of endosomal maturation

TOM1 is a PI5P effector involved in the regulation of endosomal maturation

In B cells, phosphatidylinositol 5-phosphate 4-kinase–α synthesizes PI(4,5)P₂to impact mTORC2 and Akt signaling

Les phosphoinositides

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Phosphatidylinositol 5‐phosphate: A nuclear stress lipid and a tuner of membranes and cytoskeleton dynamics

Cited by 39 publications

References 104 publications

TOM1 is a PI5P effector involved in the regulation of endosomal maturation

TOM1 is a PI5P effector involved in the regulation of endosomal maturation

In B cells, phosphatidylinositol 5-phosphate 4-kinase–α synthesizes PI(4,5)P2to impact mTORC2 and Akt signaling

Les phosphoinositides

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In B cells, phosphatidylinositol 5-phosphate 4-kinase–α synthesizes PI(4,5)P₂to impact mTORC2 and Akt signaling