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Phosphatidylinositol 3,5-bisphosphate

February 27, 2023

Phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) is one of the seven phosphoinositides found in eukaryotic cell membranes.[1] In quiescent cells, the PtdIns(3,5)P2 levels, typically quantified by HPLC, are the lowest amongst the constitutively present phosphoinositides. They are approximately 3 to 5-fold lower as compared to PtdIns3P and PtdIns5P (Phosphatidylinositol 5-phosphate) levels, and more than 100-fold lower than the abundant PtdIns4P (Phosphatidylinositol 4-phosphate) and PtdIns(4,5)P2.[2] PtdIns(3,5)P2 was first reported to occur in mouse fibroblasts and budding yeast S. cerevisiae in 1997.[3][4] In S. cerevisiae PtdIns(3,5)P2 levels increase dramatically during hyperosmotic shock.[4] The response to hyperosmotic challenge is not conserved in most tested mammalian cells except for differentiated 3T3L1 adipocytes. [4][5]

Metabolism

The only currently known pathway for PtdIns(3,5)P2 production is through synthesis catalyzed by the phosphoinositide kinase PIKfyve. Pulse-chase experiments in mouse fibroblasts reveal that PtdIns(3,5)P2 is reverted to PtdIns3P soon after its synthesis.[3] In mammalian cells, PtdIns(3,5)P2 is synthesized from and turned over to PtdIns3P by a unique protein complex containing two enzymes with opposite activities: the phosphoinositide kinase PIKfyve and the Sac1 domain-containing PtdIns(3,5)P2 5-phosphatase, Sac3/Fig4.[6] The two enzymes do not interact directly. Rather, they are brought together by an associated regulator of PIKfyve, called ArPIKfyve/VAC14, that scaffolds a ternary regulatory complex, known as the PAS complex (from the first letters of PIKfyve/ArPIKfyve/Sac3).[7] PIKfyve attaches the PAS complex onto Rab5GTP/PtdIns3P-enriched endosomal microdomains via its FYVE finger domain that selectively binds PtdIns3P. [8][9][10] The essential role of the PAS complex in PtdIns(3,5)P2 synthesis and turnover is supported by data from siRNA-mediated protein silencing and heterologous expression of the PAS complex components in various cell types as well as by data from genetic knockout of the PAS complex proteins. [5][6][11][12][13][14][15]

An additional pathway for PtdIns(3,5)P2 turnover involves the myotubularin family of phosphatases. Myotubularin 1 and MTMR2 dephosphorylate the 3-position of PtdIns(3,5)P2; therefore, the product of this hydrolysis is PtdIns5P, rather than PtdIns3P. [16] The PAS complex proteins are evolutionarily conserved with orthologs found in S. cerevisiae (i.e., Fab1p, Vac14p, and Fig4p proteins) as well as in all eukaryotes with sequenced genomes. Therefore, it is believed that PtdIns(3,5)P2 is present in all eukaryotes where it regulates similar cellular functions. Yeast Fab1p, Vac14p, and Fig4p also form a complex, called the Fab1 complex. [17] However, the Fab1 complex contains additional proteins, [18] which might add an additional layer of PtdIns(3,5)P2 regulation in yeast. The composition of the protein complexes regulating PtdIns(3,5)P2 levels in other species is yet to be clarified.

Functions and regulation

PtdIns(3,5)P2 regulates endosomal operations (fission and fusion) that maintain endomembrane homeostasis and proper performance of the trafficking pathways emanating from or traversing endosomes. Decrease of PtdIns(3,5)P2 levels upon perturbations of cellular PIKfyve by heterologous expression of enzymatically inactive PIKfyve point mutants, [19] siRNA-medicated silencing, [20] pharmacological inhibition [21] and PIKFYVE knockout [13] all cause formation of multiple cytosolic vacuoles, which become larger over time. Importantly, the vacuolation induced by PIKfyve dysfunction and PtdIns(3,5)P2 depletion is reversible and could be selectively rescued by cytosolic microinjection of PtdIns(3,5)P2, [22] overexpression of PIKfyve [19] or wash-out of the PIKfyve inhibitor YM201636. [21] Sac3 phosphatase activity in the PAS complex also plays an important role in regulating PtdIns(3,5)P2 levels and maintaining endomembrane homeostasis. Thus, cytoplasmic vacuolation induced by the dominant-negative PIKfyveK1831E mutant is suppressed upon co-expression of a Sac3 phosphatase-inactive point-mutant along with ArPIKfyve. [12] In vitro reconstitution assays of endosome fusion and multivesicular body (MVB) formation/detachment (fission) suggest a positive role of PtdIns(3,5)P2 in MVB fission from maturing early endosomes and a negative role in endosome fusion. [6][8] PtdIns(3,5)P2 is implicated in the microtubule-dependent retrograde transport from early/late endosomes to the trans Golgi network. [20][23]

Acute insulin treatment increases PtdIns(3,5)P2 levels in 3T3L1 adipocytes, both in isolated membranes and intact cells to promote insulin effect on GLUT4 cell surface translocation and glucose transport. [11][12] These cells also show a marked PtdIns(3,5)P2 increase upon hyperosmotic shock. [5] Other stimuli, including mitogenic signals such as IL-2 and UV light in lymphocytes, [24] activation of protein kinase C by PMA in platelets [25] and EGF stimulation of COS cells, [26] also increase PtdIns(3,5)P2 levels.

PtdIns(3,5)P2 plays a key role in growth and development as evidenced by the preimplantation lethality of the PIKfyve knockout mouse model. [13] The fact that the heterozygous PIKfyve mice are ostensibly normal and live to late adulthood with only ~60% of the wild-type PtdIns(3,5)P2 levels suggests that PtdIns(3,5)P2 might normally be in excess. [13]

ArPIKfyve/Vac14 or Sac3/Fig4 knockout in mice results in a 30-50% decrease in PtdIns(3,5)P2 levels and cause similar massive central neurodegeneration and peripheral neuropathy. [14][15] These studies suggest that reduced PtdIns(3,5)P2 levels, by a yet-to-be identified mechanism, mediate neuronal death. In contrast, MTMR2 phosphatase knockout, which also causes peripheral neuropathy, is accompanied by elevation in PtdIns(3,5)P2. [27] Thus, whether and how the abnormal levels of PtdIns(3,5)P2 selectively affect peripheral neuronal functions remains unclear.

Effectors

Phosphoinositides are generally viewed as membrane-anchored signals recruiting specific cytosolic effector proteins. So far, several proteins have been proposed as potential PtdIns(3,5)P2 effectors. Unfortunately, the expectations that such effectors would be evolutionary conserved and share a common PtdIns(3,5)P2-binding motif of high affinity remain unfulfilled. For example, deletion of Atg18p, a protein involved also in autophagy in S. cerevisiae, causes enlarged vacuole and 10-fold elevation in PtdIns(3,5)P2. Atg18p binds PtdIns(3,5)P2 with high affinity and specificity. [28] However, except for autophagy, the mammalian orthologs of Atg18p do not share similar functions. [29] Two other yeast proteins (Ent3p and Ent5p) found in prevacuolar and endosomal structures are potential PtdIns(3,5)P2 effectors in MVB sorting. They contain a phosphoinositide-binding ENTH domain and their deletion causes MVB sorting defects resembling those reported for Fab1p deletion. [30] However, neither Ent3p nor Ent5p possess preferential and high affinity binding specificity towards PtdIns(3,5)P2 in vitro. [31] Mammalian VPS24 (a member of the charged multivesicular body proteins (CHMPs) family) is another putative PtdIns(3,5)P2 effector. [32] Alas, surface plasmon resonance measurements do not support specific or high-affinity recognition of PtdIns(3,5)P2 for both mammalian and yeast VPS24. [31] The human transmembrane cationic channel TRPML1 (whose genetic inactivation causes lysosomal storage disease) has been recently put forward as PtdIns(3,5)P2 effector, based on in vitro binding assays and its ability to rescue the vacuolation phenotype in fibroblasts from ArPIKfyve/Vac14 knockout mice. [33] But the deletion of the orthologous protein in yeast does not cause vacuole enlargement, [34] thus casting doubts about the evolutionary conservation of this effector mechanism. Further studies are needed to validate these or uncover yet unknown PtdIns(3,5)P2 effectors.

References

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External links

February 27, 2023
phosphatidylinositol, bisphosphate, ptdins, seven, phosphoinositides, found, eukaryotic, cell, membranes, quiescent, cells, ptdins, levels, typically, quantified, hplc, lowest, amongst, constitutively, present, phosphoinositides, they, approximately, fold, low. Phosphatidylinositol 3 5 bisphosphate PtdIns 3 5 P2 is one of the seven phosphoinositides found in eukaryotic cell membranes 1 In quiescent cells the PtdIns 3 5 P2 levels typically quantified by HPLC are the lowest amongst the constitutively present phosphoinositides They are approximately 3 to 5 fold lower as compared to PtdIns3P and PtdIns5P Phosphatidylinositol 5 phosphate levels and more than 100 fold lower than the abundant PtdIns4P Phosphatidylinositol 4 phosphate and PtdIns 4 5 P2 2 PtdIns 3 5 P2 was first reported to occur in mouse fibroblasts and budding yeast S cerevisiae in 1997 3 4 In S cerevisiae PtdIns 3 5 P2 levels increase dramatically during hyperosmotic shock 4 The response to hyperosmotic challenge is not conserved in most tested mammalian cells except for differentiated 3T3L1 adipocytes 4 5 Contents 1 Metabolism 2 Functions and regulation 3 Effectors 4 References 5 External linksMetabolism EditThe only currently known pathway for PtdIns 3 5 P2 production is through synthesis catalyzed by the phosphoinositide kinase PIKfyve Pulse chase experiments in mouse fibroblasts reveal that PtdIns 3 5 P2 is reverted to PtdIns3P soon after its synthesis 3 In mammalian cells PtdIns 3 5 P2 is synthesized from and turned over to PtdIns3P by a unique protein complex containing two enzymes with opposite activities the phosphoinositide kinase PIKfyve and the Sac1 domain containing PtdIns 3 5 P2 5 phosphatase Sac3 Fig4 6 The two enzymes do not interact directly Rather they are brought together by an associated regulator of PIKfyve called ArPIKfyve VAC14 that scaffolds a ternary regulatory complex known as the PAS complex from the first letters of PIKfyve ArPIKfyve Sac3 7 PIKfyve attaches the PAS complex onto Rab5GTP PtdIns3P enriched endosomal microdomains via its FYVE finger domain that selectively binds PtdIns3P 8 9 10 The essential role of the PAS complex in PtdIns 3 5 P2 synthesis and turnover is supported by data from siRNA mediated protein silencing and heterologous expression of the PAS complex components in various cell types as well as by data from genetic knockout of the PAS complex proteins 5 6 11 12 13 14 15 An additional pathway for PtdIns 3 5 P2 turnover involves the myotubularin family of phosphatases Myotubularin 1 and MTMR2 dephosphorylate the 3 position of PtdIns 3 5 P2 therefore the product of this hydrolysis is PtdIns5P rather than PtdIns3P 16 The PAS complex proteins are evolutionarily conserved with orthologs found in S cerevisiae i e Fab1p Vac14p and Fig4p proteins as well as in all eukaryotes with sequenced genomes Therefore it is believed that PtdIns 3 5 P2 is present in all eukaryotes where it regulates similar cellular functions Yeast Fab1p Vac14p and Fig4p also form a complex called the Fab1 complex 17 However the Fab1 complex contains additional proteins 18 which might add an additional layer of PtdIns 3 5 P2 regulation in yeast The composition of the protein complexes regulating PtdIns 3 5 P2 levels in other species is yet to be clarified Functions and regulation EditPtdIns 3 5 P2 regulates endosomal operations fission and fusion that maintain endomembrane homeostasis and proper performance of the trafficking pathways emanating from or traversing endosomes Decrease of PtdIns 3 5 P2 levels upon perturbations of cellular PIKfyve by heterologous expression of enzymatically inactive PIKfyve point mutants 19 siRNA medicated silencing 20 pharmacological inhibition 21 and PIKFYVE knockout 13 all cause formation of multiple cytosolic vacuoles which become larger over time Importantly the vacuolation induced by PIKfyve dysfunction and PtdIns 3 5 P2 depletion is reversible and could be selectively rescued by cytosolic microinjection of PtdIns 3 5 P2 22 overexpression of PIKfyve 19 or wash out of the PIKfyve inhibitor YM201636 21 Sac3 phosphatase activity in the PAS complex also plays an important role in regulating PtdIns 3 5 P2 levels and maintaining endomembrane homeostasis Thus cytoplasmic vacuolation induced by the dominant negative PIKfyveK1831E mutant is suppressed upon co expression of a Sac3 phosphatase inactive point mutant along with ArPIKfyve 12 In vitro reconstitution assays of endosome fusion and multivesicular body MVB formation detachment fission suggest a positive role of PtdIns 3 5 P2 in MVB fission from maturing early endosomes and a negative role in endosome fusion 6 8 PtdIns 3 5 P2 is implicated in the microtubule dependent retrograde transport from early late endosomes to the trans Golgi network 20 23 Acute insulin treatment increases PtdIns 3 5 P2 levels in 3T3L1 adipocytes both in isolated membranes and intact cells to promote insulin effect on GLUT4 cell surface translocation and glucose transport 11 12 These cells also show a marked PtdIns 3 5 P2 increase upon hyperosmotic shock 5 Other stimuli including mitogenic signals such as IL 2 and UV light in lymphocytes 24 activation of protein kinase C by PMA in platelets 25 and EGF stimulation of COS cells 26 also increase PtdIns 3 5 P2 levels PtdIns 3 5 P2 plays a key role in growth and development as evidenced by the preimplantation lethality of the PIKfyve knockout mouse model 13 The fact that the heterozygous PIKfyve mice are ostensibly normal and live to late adulthood with only 60 of the wild type PtdIns 3 5 P2 levels suggests that PtdIns 3 5 P2 might normally be in excess 13 ArPIKfyve Vac14 or Sac3 Fig4 knockout in mice results in a 30 50 decrease in PtdIns 3 5 P2 levels and cause similar massive central neurodegeneration and peripheral neuropathy 14 15 These studies suggest that reduced PtdIns 3 5 P2 levels by a yet to be identified mechanism mediate neuronal death In contrast MTMR2 phosphatase knockout which also causes peripheral neuropathy is accompanied by elevation in PtdIns 3 5 P2 27 Thus whether and how the abnormal levels of PtdIns 3 5 P2 selectively affect peripheral neuronal functions remains unclear Effectors EditPhosphoinositides are generally viewed as membrane anchored signals recruiting specific cytosolic effector proteins So far several proteins have been proposed as potential PtdIns 3 5 P2 effectors Unfortunately the expectations that such effectors would be evolutionary conserved and share a common PtdIns 3 5 P2 binding motif of high affinity remain unfulfilled For example deletion of Atg18p a protein involved also in autophagy in S cerevisiae causes enlarged vacuole and 10 fold elevation in PtdIns 3 5 P2 Atg18p binds PtdIns 3 5 P2 with high affinity and specificity 28 However except for autophagy the mammalian orthologs of Atg18p do not share similar functions 29 Two other yeast proteins Ent3p and Ent5p found in prevacuolar and endosomal structures are potential PtdIns 3 5 P2 effectors in MVB sorting They contain a phosphoinositide binding ENTH domain and their deletion causes MVB sorting defects resembling those reported for Fab1p deletion 30 However neither Ent3p nor Ent5p possess preferential and high affinity binding specificity towards PtdIns 3 5 P2 in vitro 31 Mammalian VPS24 a member of the charged multivesicular body proteins CHMPs family is another putative PtdIns 3 5 P2 effector 32 Alas surface plasmon resonance measurements do not support specific or high affinity recognition of PtdIns 3 5 P2 for both mammalian and yeast VPS24 31 The human transmembrane cationic channel TRPML1 whose genetic inactivation causes lysosomal storage disease has been recently put forward as PtdIns 3 5 P2 effector based on in vitro binding assays and its ability to rescue the vacuolation phenotype in fibroblasts from ArPIKfyve Vac14 knockout mice 33 But the deletion of the orthologous protein in yeast does not cause vacuole enlargement 34 thus casting doubts about the evolutionary conservation of this effector mechanism Further studies are needed to validate these or uncover yet unknown PtdIns 3 5 P2 effectors References Edit Di Paolo G De Camilli P Phosphoinositides in cell regulation and membrane dynamics Nature 2006 Oct 12 443 7112 651 7 PMID 17035995 Shisheva A Regulating Glut4 vesicle dynamics by phosphoinositide kinases and phosphoinositide phosphatases Front Biosci 2003 Sep 1 8 s945 56 Review PMID 12957825 a b Whiteford CC Brearley CA Ulug ET Phosphatidylinositol 3 5 bisphosphate defines a novel PI 3 kinase pathway in resting mouse fibroblasts Biochem J 1997 May 1 323 Pt 3 597 601 PMID 9169590 a b c Dove SK Cooke FT Douglas MR Sayers LG Parker PJ Michell RH Osmotic stress activates phosphatidylinositol 3 5 bisphosphate synthesis Nature 1997 Nov 13 390 6656 187 92 PMID 9367158 a b c Sbrissa D Shisheva A Acquisition of unprecedented phosphatidylinositol 3 5 bisphosphate rise in hyperosmotically stressed 3T3 L1 adipocytes mediated by ArPIKfyve PIKfyve pathway J Biol Chem 2005 Mar 4 280 9 7883 9 Epub 2004 Nov 16 PMID 15546865 a b c Sbrissa D Ikonomov OC Fu Z Ijuin T Gruenberg J Takenawa T Shisheva A Core protein machinery for mammalian phosphatidylinositol 3 5 bisphosphate synthesis and turnover that 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XP Shen D Wang X Dawson T Li X Zhang Q Cheng X Zhang Y Weisman LS Delling M Xu H PI 3 5 P 2 controls membrane trafficking by direct activation of mucolipin Ca 2 release channels in the endolysosome Nat Commun 2010 Jul 13 1 38 doi 10 1038 ncomms1037 PMID 20802798 Chang Y Schlenstedt G Flockerzi V Beck A Properties of the intracellular transient receptor potential TRP channel in yeast Yvc1 FEBS Lett 2010 May 17 584 10 2028 32 Epub 2009 Dec 24 PMID 20035756External links Editphosphatidylinositol 3 5 bisphosphate at the US National Library of Medicine Medical Subject Headings MeSH Retrieved from https en wikipedia org w index php title Phosphatidylinositol 3 5 bisphosphate amp oldid 1124857992, wikipedia, wiki, book, books, library,

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