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]

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

  1. ↑ Di Paolo G, De Camilli P. Phosphoinositides in cell regulation and membrane dynamics. Nature. 2006 Oct 12;443(7112):651-7. PMID 17035995
  2. ↑ Shisheva A. Regulating Glut4 vesicle dynamics by phosphoinositide kinases and phosphoinositide phosphatases. Front Biosci. 2003 Sep 1;8:s945-56. Review. PMID 12957825
  3. 1 2 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
  4. 1 2 3 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
  5. 1 2 3 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
  6. 1 2 3 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 regulates the progression of endosomal transport. Novel Sac phosphatase joins the ArPIKfyve-PIKfyve complex. J Biol Chem. 2007 Aug 17;282(33):23878-91. Epub 2007 Jun 7. doi:10.1074/jbc.M611678200 PMID 17556371
  7. ↑ Sbrissa D, Ikonomov OC, Fenner H, Shisheva A. ArPIKfyve homomeric and heteromeric interactions scaffold PIKfyve and Sac3 in a complex to promote PIKfyve activity and functionality. J Mol Biol. 2008 Dec 26;384(4):766-79. Epub 2008 Oct 11. doi:10.1016/j.jmb.2008.10.009 PMID 18950639
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  9. ↑ Shisheva A, Sbrissa D, Ikonomov O. Cloning, characterization, and expression of a novel Zn2+-binding FYVE finger-containing phosphoinositide kinase in insulin-sensitive cells. Mol Cell Biol. 1999 Jan; 19(1):623-34. PMID 9858586
  10. ↑ Sbrissa D, Ikonomov OC, Shisheva A. Phosphatidylinositol 3-phosphate-interacting domains in PIKfyve. Binding specificity and role in PIKfyve. Endomenbrane localization. J Biol Chem. 2002 Feb 22;277(8):6073-9. Epub 2001 Nov 12. doi:10.1074/jbc.M110194200 PMID 11706043
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  13. 1 2 3 4 Ikonomov OC, Sbrissa D, Delvecchio K, Xie Y, Jin JP, Rappolee D, Shisheva A. The phosphoinositide kinase PIKfyve is vital in early embryonic development: preimplantation lethality of PIKfyve-/- embryos but normality of PIKfyve+/- mice. J Biol Chem. 2011 Apr 15;286(15):13404-13. Epub 2011 Feb 24. doi:10.1074/jbc.M111.222364 PMID 21349843
  14. 1 2 Zhang Y, Zolov SN, Chow CY, Slutsky SG, Richardson SC, Piper RC, Yang B, Nau JJ, Westrick RJ, Morrison SJ, Meisler MH, Weisman LS. Loss of Vac14, a regulator of the signaling lipid phosphatidylinositol 3,5-bisphosphate, results in neurodegeneration in mice. Proc Natl Acad Sci U S A. 2007 Oct 30;104(44):17518-23. Epub 2007 Oct 23.PMID 17956977
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  16. ↑ Shisheva A. PIKfyve: Partners, significance, debates and paradoxes. Cell Biol Int. 2008 Jun;32(6):591-604. Epub 2008 Jan 25. Review. doi:10.1016/j.cellbi.2008.01.006 PMID 18304842
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  27. ↑ Vaccari I, Dina G, Tronchère H, Kaufman E, Chicanne G, Cerri F, Wrabetz L, Payrastre B, Quattrini A, Weisman LS, Meisler MH, Bolino A. Genetic interaction between MTMR2 and FIG4 phospholipid phosphatases involved in Charcot-Marie-Tooth neuropathies. PLoS Genet. 2011 Oct;7(10):e1002319. Epub 2011 Oct 20. PMID 22028665
  28. ↑ Dove SK, Piper RC, McEwen RK, Yu JW, King MC, Hughes DC, Thuring J, Holmes AB, Cooke FT, Michell RH, Parker PJ, Lemmon MA. Svp1p defines a family of phosphatidylinositol 3,5-bisphosphate effectors. EMBO J. 2004 May 5;23(9):1922-33. Epub 2004 Apr 22. PMID 15103325
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  30. ↑ Friant S, Pécheur EI, Eugster A, Michel F, Lefkir Y, Nourrisson D, Letourneur F. Ent3p Is a PtdIns(3,5)P2 effector required for protein sorting to the multivesicular body. Dev Cell. 2003 Sep;5(3):499-511. PMID 12967568
  31. 1 2 Michell RH, Heath VL, Lemmon MA, Dove SK. Phosphatidylinositol 3,5-bisphosphate: metabolism and cellular functions. Trends Biochem Sci. 2006 Jan;31(1):52-63. Epub 2005 Dec 20. Review. doi:10.1016/j.tibs.2005.11.013 PMID 16364647
  32. ↑ Whitley P, Reaves BJ, Hashimoto M, Riley AM, Potter BV, Holman GD. Identification of mammalian Vps24p as an effector of phosphatidylinositol 3,5-bisphosphate-dependent endosome compartmentalization. J Biol Chem. 2003 Oct 3;278(40):38786-95. Epub 2003 Jul 23. PMID 12878588
  33. ↑ Dong 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
  34. ↑ 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 20035756
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