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PMID: 20802798 Published · epublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

PI(3,5)P(2) controls membrane trafficking by direct activation of mucolipin Ca(2+) release channels in the endolysosome.

Nature communications ·Vol. 1 ·2010-07-13 ·Pages 38

Dong XP, Shen D, Wang X, Dawson T, Li X, Zhang Q, Cheng X, Zhang Y, Weisman LS, Delling M, Xu H

Abstract

Membrane fusion and fission events in intracellular trafficking are controlled by both intraluminal Ca(2+) release and phosphoinositide (PIP) signalling. However, the molecular identities of the Ca(2+) release channels and the target proteins of PIPs are elusive. In this paper, by direct patch-clamping of the endolysosomal membrane, we report that PI(3,5)P(2), an endolysosome-specific PIP, binds and activates endolysosome-localized mucolipin transient receptor potential (TRPML) channels with specificity and potency. Both PI(3,5)P(2)-deficient cells and cells that lack TRPML1 exhibited enlarged endolysosomes/vacuoles and trafficking defects in the late endocytic pathway. We find that the enlarged vacuole phenotype observed in PI(3,5)P(2)-deficient mouse fibroblasts is suppressed by overexpression of TRPML1. Notably, this PI(3,5)P(2)-dependent regulation of TRPML1 is evolutionarily conserved. In budding yeast, hyperosmotic stress induces Ca(2+) release from the vacuole. In this study, we show that this release requires both PI(3,5)P(2) production and a yeast functional TRPML homologue. We propose that TRPMLs regulate membrane trafficking by transducing information regarding PI(3,5)P(2) levels into changes in juxtaorganellar Ca(2+), thereby triggering membrane fusion/fission events.

Keywords
Ca2+ release channel Fab1 PI(3 5)P2 PIKfyve TRP channel Whole-endolysosome recording endosome lysosome membrane trafficking phosphoinositide type IV Mucolipidosis vacuole
MeSH Terms
Animals Biological Transport Cell Membrane/metabolism Electrophysiology Intracellular Signaling Peptides and Proteins/metabolism Lysosomes/metabolism Membrane Proteins Mice Phosphatidylinositol Phosphates/metabolism Protein Binding TRPM Cation Channels/metabolism Transient Receptor Potential Channels
Chemicals
Intracellular Signaling Peptides and Proteins Mcoln2 protein, mouse Membrane Proteins Phosphatidylinositol Phosphates TRPM Cation Channels Transient Receptor Potential Channels Vac14 protein, mouse phosphatidylinositol 3,5-diphosphate
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Dong Xian-ping
Department of Molecular, Cellular, and Developmental Biology, University of Michigan, 3089 National Science Building (Kraus), 830 North University, Ann Arbor, Michigan 48109, USA.
Shen Dongbiao
Wang Xiang
Dawson Taylor
Li Xinran
Zhang Qi
Cheng Xiping
Zhang Yanling
Weisman Lois S
Delling Markus
Xu Haoxing
References (45)
45 references, click to expand
  1. TRP channels of intracellular membranes.
    J Neurochem. 2010 Apr;113(2):313-28 PMID: 20132470
  2. NAADP mobilizes calcium from acidic organelles through two-pore channels.
    Nature. 2009 May 28;459(7246):596-600 PMID: 19387438
  3. The stress-activated phosphatidylinositol 3-phosphate 5-kinase Fab1p is essential for vacuole function in S. cerevisiae.
    Curr Biol. 1998 Nov 5;8(22):1219-22 PMID: 9811604
  4. Mucolipins: Intracellular TRPML1-3 channels.
    FEBS Lett. 2010 May 17;584(10):2013-21 PMID: 20074572
  5. VAC14 nucleates a protein complex essential for the acute interconversion of PI3P and PI(3,5)P(2) in yeast and mouse.
    EMBO J. 2008 Dec 17;27(24):3221-34 PMID: 19037259
  6. Ca2+/calmodulin signals the completion of docking and triggers a late step of vacuole fusion.
    Nature. 1998 Dec 10;396(6711):575-80 PMID: 9859992
  7. Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J.
    Nature. 2007 Jul 5;448(7149):68-72 PMID: 17572665
  8. Calcium: a fundamental regulator of intracellular membrane fusion?
    EMBO Rep. 2007 Mar;8(3):236-40 PMID: 17330068
  9. Assembly of a Fab1 phosphoinositide kinase signaling complex requires the Fig4 phosphoinositide phosphatase.
    Mol Biol Cell. 2008 Oct;19(10):4273-86 PMID: 18653468
  10. Deficiency of MIP/MTMR14 phosphatase induces a muscle disorder by disrupting Ca(2+) homeostasis.
    Nat Cell Biol. 2009 Jun;11(6):769-76 PMID: 19465920
  11. Role of the V-ATPase in regulation of the vacuolar fission-fusion equilibrium.
    Mol Biol Cell. 2007 Oct;18(10):3873-82 PMID: 17652457
  12. 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 PMID: 17956977
  13. Lysosomal trafficking functions of mucolipin-1 in murine macrophages.
    BMC Cell Biol. 2007 Dec 21;8:54 PMID: 18154673
  14. Mucolipidosis type IV is caused by mutations in a gene encoding a novel transient receptor potential channel.
    Hum Mol Genet. 2000 Oct 12;9(17):2471-8 PMID: 11030752
  15. A phosphoinositide switch controls the maturation and signaling properties of APPL endosomes.
    Cell. 2009 Mar 20;136(6):1110-21 PMID: 19303853
  16. Integration of phosphoinositide- and calmodulin-mediated regulation of TRPC6.
    Mol Cell. 2007 Feb 23;25(4):491-503 PMID: 17317623
  17. Phosphoinositide 5-phosphatase Fig 4p is required for both acute rise and subsequent fall in stress-induced phosphatidylinositol 3,5-bisphosphate levels.
    Eukaryot Cell. 2006 Apr;5(4):723-31 PMID: 16607019
  18. Mucolipin-1 is a lysosomal membrane protein required for intracellular lactosylceramide traffic.
    Traffic. 2006 Oct;7(10):1388-98 PMID: 16978393
  19. TPCs: Endolysosomal channels for Ca2+ mobilization from acidic organelles triggered by NAADP.
    FEBS Lett. 2010 May 17;584(10):1966-74 PMID: 20159015
  20. Caenorhabditis elegans functional orthologue of human protein h-mucolipin-1 is required for lysosome biogenesis.
    Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4483-8 PMID: 15070744
  21. A potentially dynamic lysosomal role for the endogenous TRPML proteins.
    J Pathol. 2009 Oct;219(2):153-62 PMID: 19557826
  22. A helix-breaking mutation in TRPML3 leads to constitutive activity underlying deafness in the varitint-waddler mouse.
    Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19583-8 PMID: 18048323
  23. Vacuole size control: regulation of PtdIns(3,5)P2 levels by the vacuole-associated Vac14-Fig4 complex, a PtdIns(3,5)P2-specific phosphatase.
    Mol Biol Cell. 2004 Jan;15(1):24-36 PMID: 14528018
  24. Identification of the penta-EF-hand protein ALG-2 as a Ca2+-dependent interactor of mucolipin-1.
    J Biol Chem. 2009 Dec 25;284(52):36357-36366 PMID: 19864416
  25. PIP2 is a necessary cofactor for ion channel function: how and why?
    Annu Rev Biophys. 2008;37:175-95 PMID: 18573078
  26. The small chemical vacuolin-1 alters the morphology of lysosomes without inhibiting Ca2+-regulated exocytosis.
    EMBO Rep. 2005 Sep;6(9):843-7 PMID: 16113649
  27. Phosphatidylinositol 3,5-bisphosphate and Fab1p/PIKfyve underPPIn endo-lysosome function.
    Biochem J. 2009 Apr 1;419(1):1-13 PMID: 19272020
  28. Activating mutations of the TRPML1 channel revealed by proline-scanning mutagenesis.
    J Biol Chem. 2009 Nov 13;284(46):32040-52 PMID: 19638346
  29. Transient receptor potential cation channels in disease.
    Physiol Rev. 2007 Jan;87(1):165-217 PMID: 17237345
  30. The Ca(2+) channel TRPML3 regulates membrane trafficking and autophagy.
    Traffic. 2009 Aug;10(8):1157-67 PMID: 19522758
  31. Internal Ca(2+) release in yeast is triggered by hypertonic shock and mediated by a TRP channel homologue.
    J Cell Biol. 2002 Jan 7;156(1):29-34 PMID: 11781332
  32. Transient receptor potential channels meet phosphoinositides.
    EMBO J. 2008 Nov 5;27(21):2809-16 PMID: 18923420
  33. Osmotic stress-induced increase of phosphatidylinositol 3,5-bisphosphate requires Vac14p, an activator of the lipid kinase Fab1p.
    J Cell Biol. 2002 Mar 18;156(6):1015-28 PMID: 11889142
  34. The type IV mucolipidosis-associated protein TRPML1 is an endolysosomal iron release channel.
    Nature. 2008 Oct 16;455(7215):992-6 PMID: 18794901
  35. The Vac14p-Fig4p complex acts independently of Vac7p and couples PI3,5P2 synthesis and turnover.
    J Cell Biol. 2006 Feb 27;172(5):693-704 PMID: 16492811
  36. Activating mutation in a mucolipin transient receptor potential channel leads to melanocyte loss in varitint-waddler mice.
    Proc Natl Acad Sci U S A. 2007 Nov 13;104(46):18321-6 PMID: 17989217
  37. Phosphoinositides in constitutive membrane traffic.
    Physiol Rev. 2004 Jul;84(3):699-730 PMID: 15269334
  38. TRPMLs: in sickness and in health.
    Am J Physiol Renal Physiol. 2009 Jun;296(6):F1245-54 PMID: 19158345
  39. Abnormal transport along the lysosomal pathway in mucolipidosis, type IV disease.
    Proc Natl Acad Sci U S A. 1998 May 26;95(11):6373-8 PMID: 9600972
  40. Phosphatidylinositol metabolism and membrane fusion.
    Biochem J. 2009 Mar 1;418(2):233-46 PMID: 19196244
  41. A TRP homolog in Saccharomyces cerevisiae forms an intracellular Ca(2+)-permeable channel in the yeast vacuolar membrane.
    Proc Natl Acad Sci U S A. 2001 Jul 3;98(14):7801-5 PMID: 11427713
  42. Fab1p is essential for PtdIns(3)P 5-kinase activity and the maintenance of vacuolar size and membrane homeostasis.
    J Cell Biol. 1998 Oct 5;143(1):65-79 PMID: 9763421
  43. Lysosomes: fusion and function.
    Nat Rev Mol Cell Biol. 2007 Aug;8(8):622-32 PMID: 17637737
  44. Deleterious variants of FIG4, a phosphoinositide phosphatase, in patients with ALS.
    Am J Hum Genet. 2009 Jan;84(1):85-8 PMID: 19118816
  45. Defective autophagy in neurons and astrocytes from mice deficient in PI(3,5)P2.
    Hum Mol Genet. 2009 Dec 15;18(24):4868-78 PMID: 19793721
Article Info
Journal
Nature communications
Abbr.
Nat Commun
ISSN
2041-1723
DOI
10.1038/ncomms1037
Published
2010-07-13
Epub
2010-00-13
Pages
38
Language
English
Region
England
NLM ID
101528555
PMCID
PMC2928581
Subset
IM
Grants
NINDS NIH HHS · R01 NS062792 · United States
NINDS NIH HHS · R01 NS062792-02 · United States
NIGMS NIH HHS · R01 GM050403 · United States
NINDS NIH HHS · R01 NS064015 · United States
NIGMS NIH HHS · R01 GM50403 · United States
External Links
PubMed source DOI: 10.1038/ncomms1037 PMC Full Text View journal details
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