Phosphatidylinositol 3,5-bisphosphate

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Phosphatidylinositol 3,5-bisphosphate 2d representation

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

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.

Related Research Articles

<span class="mw-page-title-main">Phosphatidylinositol</span> Chemical compound

Phosphatidylinositol consists of a family of lipids made of a phosphate group, two fatty acid chains, and one inositol molecule. They represent a class of the phosphatidylglycerides. Typically phosphatidylinositols form a minor component on the cytosolic side of eukaryotic cell membranes. The phosphate group gives the molecules a negative charge at physiological pH.

<span class="mw-page-title-main">Phosphoinositide 3-kinase</span> Class of enzymes

Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer.

<span class="mw-page-title-main">Phosphatidylinositol 4,5-bisphosphate</span> Chemical compound

Phosphatidylinositol 4,5-bisphosphate or PtdIns(4,5)P2, also known simply as PIP2 or PI(4,5)P2, is a minor phospholipid component of cell membranes. PtdIns(4,5)P2 is enriched at the plasma membrane where it is a substrate for a number of important signaling proteins. PIP2 also forms lipid clusters that sort proteins.

<span class="mw-page-title-main">Phosphatidylinositol 3-phosphate</span> Chemical compound

Phosphatidylinositol 3-phosphate (PtdIns3P) is a phospholipid found in cell membranes that helps to recruit a range of proteins, many of which are involved in protein trafficking, to the membranes. It is the product of both the class II and III phosphoinositide 3-kinases activity on phosphatidylinositol.

<span class="mw-page-title-main">Phosphatidylinositol 3,4-bisphosphate</span>

Phosphatidylinositol (3,4)-bisphosphate is a minor phospholipid component of cell membranes, yet an important second messenger. The generation of PtdIns(3,4)P2 at the plasma membrane activates a number of important cell signaling pathways.

Phosphatidylinositol phosphate kinases (PIPK) are kinases that phosphorylate the phosphoinositides PtdInsP and PtdInsP2 that are derivatives of phosphatidylinositol (PtdIns). It has been found that PtdIns is only phosphorylated on three (3,4,5) of its five hydroxyl groups, possibly because D-2 and D-6 hydroxyl groups cannot be phosphorylated because of steric hindrance. All 7 combinations of phosphorylated PtdIns have been found in animals, all except PtdIns(3,4,5)P3 have been found in plants.

<span class="mw-page-title-main">PX domain</span>

The PX domain is a phosphoinositide-binding structural domain involved in targeting of proteins to cell membranes.

<span class="mw-page-title-main">Yunis–Varon syndrome</span> Medical condition

Yunis–Varon syndrome (YVS), also called cleidocranial dysplasia with micrognathia or absent thumbs and distal aphalangia, is an extremely rare autosomal recessive multisystem congenital disorder which affects the skeletal system, ectodermal tissue, heart and respiratory system. It was first described by Emilio Yunis and Humberto Váron from the National University of Colombia.

<span class="mw-page-title-main">PIKFYVE</span> Protein-coding gene in the species Homo sapiens

PIKfyve, a FYVE finger-containing phosphoinositide kinase, is an enzyme that in humans is encoded by the PIKFYVE gene.

<span class="mw-page-title-main">PIP5K1A</span> Protein-coding gene in the species Homo sapiens

Phosphatidylinositol-4-phosphate 5-kinase type-1 alpha is an enzyme that in humans is encoded by the PIP5K1A gene.

<span class="mw-page-title-main">PLEKHA1</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">RABEPK</span> Protein-coding gene in the species Homo sapiens

Rab9 effector protein with Kelch motifs also known as p40 is a protein that in humans is encoded by the RABEPK gene.

Bisphosphate may refer to:

Phosphatidylinositol 5-phosphate (PtdIns5P) is a phosphoinositide, one of the phosphorylated derivatives of phosphatidylinositol (PtdIns), that are well-established membrane-anchored regulatory molecules. Phosphoinositides participate in signaling events that control cytoskeletal dynamics, intracellular membrane trafficking, cell proliferation and many other cellular functions. Generally, phosphoinositides transduce signals by recruiting specific phosphoinositide-binding proteins to intracellular membranes.

Lewis C. Cantley is an American cell biologist and biochemist who has made significant advances to the understanding of cancer metabolism. Among his most notable contributions are the discovery and study of the enzyme PI-3-kinase, now known to be important to understanding cancer and diabetes mellitus. He is currently Meyer Director and Professor of Cancer Biology at the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine in New York City. He was formerly a professor in the Departments of Systems Biology and Medicine at Harvard Medical School, and the Director of Cancer Research at the Beth Israel Deaconess Medical Center, in Boston, Massachusetts. In 2016, he was elected Chairman of the Board for the Hope Funds for Cancer Research.

<span class="mw-page-title-main">Fig4</span> Protein-coding gene in the species Homo sapiens

Polyphosphoinositide phosphatase also known as phosphatidylinositol 3,5-bisphosphate 5-phosphatase or SAC domain-containing protein 3 (Sac3) is an enzyme that in humans is encoded by the FIG4 gene. Fig4 is an abbreviation for Factor-Induced Gene.

<span class="mw-page-title-main">VAC14</span> Protein-coding gene in the species Homo sapiens

Protein VAC14 homolog, also known as ArPIKfyve, is a protein that in humans is encoded by the VAC14 gene.

Vacuolar segregation protein 7 is a protein that in yeast is encoded by the VAC7 gene. VAC7 is a component of the PI(3,5)P2 regulatory complex, composed of ATG18, FIG4, FAB1, VAC14 and VAC7.

Phosphatidylinositol-4,5-bisphosphate 4-phosphatase (EC 3.1.3.78, phosphatidylinositol-4,5-bisphosphate 4-phosphatase I, phosphatidylinositol-4,5-bisphosphate 4-phosphatase II, type I PtdIns-4,5-P2 4-Ptase, type II PtdIns-4,5-P2 4-Ptase, IpgD, PtdIns-4,5-P2 4-phosphatase type I, PtdIns-4,5-P2 4-phosphatase type II, type I phosphatidylinositol-4,5-bisphosphate 4-phosphatase, type 1 4-phosphatase) is an enzyme with systematic name 1-phosphatidyl-1D-myo-inositol-4,5-bisphosphate 4-phosphohydrolase. This enzyme catalyses the following chemical reaction

<span class="mw-page-title-main">Apilimod</span> Chemical compound

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