PI(5)P Regulates Autophagosome Biogenesis

Vicinanza, Mariella; Korolchuk, Viktor I.; Ashkenazi, Avraham; Puri, Claudia; Menzies, Fiona M.; Clarke, Jonathan H.; Rubinsztein, David C.

doi:10.1016/j.molcel.2014.12.007

Cited by 211 publications

(225 citation statements)

References 60 publications

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“…Accordingly, it has been reported that the genetic, siRNA, or pharmacological-mediated inhibition of PIKfyve is accompanied by an increase in PI(3)P (23)(24)(25). PIKfyve inhibition has an important impact on endosomal maturation (23,24,44,45), retrograde traffic (46), and autophagy (47,48), which collectively result in the formation of large, late endosomal compartments in which the autophagosomal marker LC3 accumulates as a result of the defective fusion with lysosomes. These features are also shared by Coxiella CCVs.…”

Section: Discussionmentioning

confidence: 99%

Coxiella burnetii effector CvpB modulates phosphoinositide metabolism for optimal vacuole development

Martínez

Allombert

Cantet

et al. 2016

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

129

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The Q fever bacterium Coxiella burnetii replicates inside host cells within a large Coxiella-containing vacuole (CCV) whose biogenesis relies on the Dot/Icm-dependent secretion of bacterial effectors. Several membrane trafficking pathways contribute membranes, proteins, and lipids for CCV biogenesis. These include the endocytic and autophagy pathways, which are characterized by phosphatidylinositol 3-phosphate [PI(3)P]-positive membranes. Here we show that the C. burnetii secreted effector Coxiella vacuolar protein B (CvpB) binds PI(3)P and phosphatidylserine (PS) on CCVs and early endosomal compartments and perturbs the activity of the phosphatidylinositol 5-kinase PIKfyve to manipulate PI(3)P metabolism. CvpB association to early endosome triggers vacuolation and clustering, leading to the channeling of large PI(3)P-positive membranes to CCVs for vacuole expansion. At CCVs, CvpB binding to early endosome-and autophagy-derived PI(3)P and the concomitant inhibition of PIKfyve favor the association of the autophagosomal machinery to CCVs for optimal homotypic fusion of the Coxiella-containing compartments. The importance of manipulating PI(3)P metabolism is highlighted by mutations in cvpB resulting in a multivacuolar phenotype, rescuable by gene complementation, indicative of a defect in CCV biogenesis. Using the insect model Galleria mellonella, we demonstrate the in vivo relevance of defective CCV biogenesis by highlighting an attenuated virulence phenotype associated with cvpB mutations.Coxiella burnetii | host-pathogen interactions | phosphoinositides

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Section: Discussionmentioning

confidence: 99%

Coxiella burnetii effector CvpB modulates phosphoinositide metabolism for optimal vacuole development

Martínez

Allombert

Cantet

et al. 2016

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

129

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“…The VPS34 complex generates PtdIns(3)P at the ER surface, which functions as a lipid platform for the recruitment of downstream effectors to initiate the phagophore membrane, such as DFCP1 and WD repeat domain, phosphoinositide interacting 2 (WIPI2) (1). However, recent evidence has argued for a role for PtdIns(5)P, instead of PtdIns(3) P, in autophagy initiation upon glucose starvation (30). The current study further expands this lipid pool to include PtdIns (4,5)P 2 , which regulates the VPS34 complex.…”

Section: Discussionmentioning

confidence: 99%

PtdIns(4,5)P ₂ signaling regulates ATG14 and autophagy

Tan

Thapa

Liao

et al. 2016

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

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Autophagy is a regulated self-digestion pathway with fundamental roles in cell homeostasis and diseases. Autophagy is regulated by coordinated actions of a series of autophagy-related (ATG) proteins. The Barkor/ATG14(L)-VPS34 (a class III phosphatidylinositol 3-kinase) complex and its product phosphatidylinositol 3-phosphate [PtdIns(3)P] play key roles in autophagy initiation. ATG14 contains a C-terminal Barkor/ATG14(L) autophagosome-targeting sequence (BATS) domain that senses the curvature of PtdIns(3)P-containing membrane. The BATS domain also strongly binds PtdIns(4,5)P 2 , but the functional significance has been unclear. Here we show that ATG14 specifically interacts with type Iγ PIP kinase isoform 5 (PIPKIγi5), an enzyme that generates PtdIns(4,5)P 2 in mammalian cells. Autophagosomes have associated PIPKIγi5 and PtdIns(4,5)P 2 that are colocalized with late endosomes and the endoplasmic reticulum. PtdIns(4,5)P 2 generation at these sites requires PIPKIγi5. Loss of PIPKIγi5 results in a loss of ATG14, UV irradiation resistance-associated gene, and Beclin 1 and a block of autophagy. PtdIns(4,5)P 2 binding to the ATG14-BATS domain regulates ATG14 interaction with VPS34 and Beclin 1, and thus plays a key role in ATG14 complex assembly and autophagy initiation. This study identifies an unexpected role for PtdIns(4,5)P 2 signaling in the regulation of ATG14 complex and autophagy.M acroautophagy (referred to as autophagy from here on) is an intracellular self-digestion process conserved in all eukaryotes that maintains cell homeostasis and protects cells from various stresses. Autophagy involves the formation of doublemembrane autophagosomes that contain target cytoplasmic contents for lysosomal degradation (1). Autophagosome formation is driven by coordinated functions of a number of autophagy-related (ATG) proteins (2). The ATG14 (also called Barkor or ATG14L)-Beclin 1 (atg6 in yeast)-VPS34 (an enzyme involved in the cellular process of autophagy; class III PI3K) complex plays essential roles in the initiation steps of autophagy by generating phosphatidylinositol 3-phosphate [PtdIns(3)P] and recruiting PtdIns(3)P effectors (3-6). ATG14 functions by recruiting VPS34 to punctate structures associated with the endoplasmic reticulum (ER) (7), and then PtdIns(3)P, the product of VPS34, in turn binds the Barkor/Atg14 autophagosome targeting sequence (BATS) domain of ATG14 and regulates its membrane curvature sensing (8). The ATG14-BATS domain also binds PtdIns(4,5)P 2 without unknown functional relevance (8).Phosphoinositides are important lipid messengers in various membrane trafficking events. PtdIns(4,5)P 2 plays multiple roles at the plasma membrane, such as in endocytosis, exocytosis, focal adhesion assembly, and so on (9). However, recently studies have argued for roles for PtdIns(4,5)P 2 at intracellular compartments (10). The majority of PtdIns(4,5)P 2 in mammalian cells are generated by the type I phosphatidylinositol 4-phosphate (PIP) 5-kinase (PIPKI), of which there are three genes (α, β, and γ) each wit...

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“…17,106 Intriguingly, PtdIns5P, produced by the type III PtdInsP 5-kinase PIKFYVE (phosphoinositide kinase, FYVE finger containing) or the phosphatase MTMR3 plays a predominant role in glucose starvationinduced autophagy, in which the role of PtdIns3P is dispensable. 106 In the case of autophagy induced in HBSS starvation medium, PtdIns5P also has a compensatory effect to sustain autophagy if PtdIns3P is depleted. 106 In particular, the noncanonical autophagy pathways stimulated by nonstarvation conditions are likely to be mediated by PtdIns3P-independent mechanisms.…”

Section: Ptdins3p Is a Key Phospholipid Required For The Progression mentioning

confidence: 99%

“…106 In the case of autophagy induced in HBSS starvation medium, PtdIns5P also has a compensatory effect to sustain autophagy if PtdIns3P is depleted. 106 In particular, the noncanonical autophagy pathways stimulated by nonstarvation conditions are likely to be mediated by PtdIns3P-independent mechanisms. [107][108][109] This emerging body of evidence points to the need to revisit the requirement of PtdIns3P for autophagy; in spite of the discrepancy, PtdIns3P is still widely accepted as a key phospholipid for the autophagic process, which remains one of the main focuses in this review.…”

Section: Ptdins3p Is a Key Phospholipid Required For The Progression mentioning

confidence: 99%

Differential regulatory functions of three classes of phosphatidylinositol and phosphoinositide 3-kinases in autophagy

2015

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Abbreviations: 3-MA, 3-methyladenine; AMBRA1, autophagy/Beclin 1 regulator 1; ATG, autophagy related; ATM, ATM serine/threonine kinase; ATR, ATR serine/threonine kinase; BH3, Bcl-2 homology 3; CCD, coiled-coil domain; CDK, cyclin-dependent kinase; CISD2, CDGSH iron sulfur domain 2; class I/II PI3K, class I/II phosphoinositide 3-kinase; class III PtdIns3K, class III phosphatidylinositol 3-kinase; DAPK1, death-associated protein kinase 1; DDR, DNA damage response; EIF4EBP1, eukaryotic translation initiation factor 4E binding protein 1; ER, endoplasmic reticulum; FOXO, forkhead box O; FYCO1, FYVE and coiledcoil domain containing 1; GAP, GTPase-activating protein; HMGB1, high mobility group box 1; HSPA1A, heat shock 70kDa protein 1A; IR, ionizing radiation; MAPK8, mitogen-activated protein kinase 8; MEFs, mouse embryonic fibroblasts; MTMR, myotubularin-related protein; MTOR, mechanistic target of rapamycin (serine/threonine kinase); MTORC1, mechanistic target of rapamycin complex 1; MVBs, spherical multivesicular bodies; NRBF2, nuclear receptor binding factor 2; PAS, phagophore assembly site; PDPK1, 3-phosphoinositide dependent protein kinase 1; PE, phosphatidylethanolamine; PIKFYVE, phosphoinositide kinase, FYVE finger containing; PINK1, PTEN-induced putative kinase 1; PtdIns3K-C1, class III phosphatidylinositol 3-kinase complex I; PtdIns3K-C2, class III phosphatidylinositol 3-kinase complex II; PKB, protein kinase B; PRKA, protein kinase, AMP-activated; PRKD1, protein kinase D1; PRKDC, protein kinase, DNA-activated, catalytic polypeptide; PtdIns5P, phosphatidylinositol 5-phosphate; PtdIns4P, phosphatidylinositol 4-phosphate; PtdIns(4,5)P 2 , phosphatidylinositol 4,5-bisphosphate; PtdIns3P, phosphatidylinositol 3-phosphate; PtdIns(3,5)P 2 , phosphatidylinositol 3,5-bisphosphate; PtdIns(3,4,5)P 3 , phosphatidylinositol 3,4,5-trisphosphate; RHEB, Ras homolog enriched in brain; RPS6KB1, ribosomal protein S6 kinase, 70kDa, polypeptide 1; SQSTM1, sequestosome 1; TECPR1, tectonin b-propeller repeat containing 1; TFEB, transcription factor EB; TRIM28, tripartite motif containing 28; TSC, tuberous sclerosis; UV, ultraviolet; UVRAG, UV radiation resistance associated; WDFY3, WD repeat and FYVE domain containing 3; WIPI, WD repeat domain, phosphoinositide interacting; ZFYVE1, zinc finger, FYVE domain containing 1.Autophagy is an evolutionarily conserved and exquisitely regulated self-eating cellular process with important biological functions. Phosphatidylinositol 3-kinases (PtdIns3Ks) and phosphoinositide 3-kinases (PI3Ks) are involved in the autophagic process. Here we aim to recapitulate how 3 classes of these lipid kinases differentially regulate autophagy. Generally, activation of the class I PI3K suppresses autophagy, via the well-established PI3K-AKT-MTOR (mechanistic target of rapamycin) complex 1 (MTORC1) pathway. In contrast, the class III PtdIns3K catalytic subunit PIK3C3/Vps34 forms a protein complex with BECN1 and PIK3R4 and produces phosphatidylinositol 3-phosphate (PtdIns3P), which is required for the initiati...

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PI(5)P Regulates Autophagosome Biogenesis

Cited by 211 publications

References 60 publications

Coxiella burnetii effector CvpB modulates phosphoinositide metabolism for optimal vacuole development

Coxiella burnetii effector CvpB modulates phosphoinositide metabolism for optimal vacuole development

PtdIns(4,5)P ₂ signaling regulates ATG14 and autophagy

Differential regulatory functions of three classes of phosphatidylinositol and phosphoinositide 3-kinases in autophagy

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PI(5)P Regulates Autophagosome Biogenesis

Cited by 211 publications

References 60 publications

Coxiella burnetii effector CvpB modulates phosphoinositide metabolism for optimal vacuole development

Coxiella burnetii effector CvpB modulates phosphoinositide metabolism for optimal vacuole development

PtdIns(4,5)P 2 signaling regulates ATG14 and autophagy

Differential regulatory functions of three classes of phosphatidylinositol and phosphoinositide 3-kinases in autophagy

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PtdIns(4,5)P ₂ signaling regulates ATG14 and autophagy