title: Defects of Vps15 in skeletal muscles lead to autophagic vacuolar myopathy and lysosomal disease.
abstract: The complex of Vacuolar Protein Sorting 34 and 15 (Vps34 and Vps15) has Class III phosphatidylinositol 3-kinase activity and putative roles in nutrient sensing, mammalian Target Of Rapamycin (mTOR) activation by amino acids, cell growth, vesicular trafficking and autophagy. Contrary to expectations, here we show that Vps15-deficient mouse tissues are competent for LC3-positive autophagosome formation and maintain mTOR activation. However, an impaired lysosomal function in mutant cells is traced by accumulation of adaptor protein p62, LC3 and Lamp2 positive vesicles, which can be reverted to normal levels after ectopic overexpression of Vps15. Mice lacking Vps15 in skeletal muscles, develop a severe myopathy. Distinct from the autophagy deficient Atg7(-/-) mutants, pathognomonic morphological hallmarks of autophagic vacuolar myopathy (AVM) are observed in Vps15(-/-) mutants, including elevated creatine kinase plasma levels, accumulation of autophagosomes, glycogen and sarcolemmal features within the fibres. Importantly, Vps34/Vps15 overexpression in myoblasts of Danon AVM disease patients alleviates the glycogen accumulation. Thus, the activity of the Vps34/Vps15 complex is critical in disease conditions such as AVMs, and possibly a variety of other lysosomal storage diseases.
authors: Inserm, U845, Paris, France.
authors: Ivan
authors: I
authors: Nemazanyy
authors: Bert
authors: B
authors: Blaauw
authors: Cecilia
authors: C
authors: Paolini
authors: Catherine
authors: C
authors: Caillaud
authors: Feliciano
authors: F
authors: Protasi
authors: Amelie
authors: A
authors: Mueller
authors: Tassula
authors: T
authors: Proikas-Cezanne
authors: Ryan C
authors: RC
authors: Russell
authors: Kun-Liang
authors: KL
authors: Guan
authors: Ichizo
authors: I
authors: Nishino
authors: Marco
authors: M
authors: Sandri
authors: Mario
authors: M
authors: Pende
authors: Ganna
authors: G
authors: Panasyuk
mesh_terms: D000818:Animals; D001343:Autophagy; D000071193:Autophagy-Related Protein 7; D002460:Cell Line; D058546:Class III Phosphatidylinositol 3-Kinases / Q000378:metabolism; D006801:Humans; D016464:Lysosomal Storage Diseases / Q000378:metabolism / Q000473:pathology; D052119:Lysosomal-Associated Membrane Protein 2 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000503:physiopathology / Q000648:ultrastructure; D009135:Muscular Diseases / Q000378:metabolism / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D051758:Transcription Factor TFIIH; D014157:Transcription Factors / Q000378:metabolism; D058571:Vacuolar Sorting Protein VPS15 / Q000235:genetics / Q000378:metabolism*
chemical_list: C502661:Atg7 protein, mouse; C490981:Gtf2h1 protein, mouse; D052119:Lysosomal-Associated Membrane Protein 2; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D014157:Transcription Factors; D051758:Transcription Factor TFIIH; D058546:Class III Phosphatidylinositol 3-Kinases; D058570:TOR Serine-Threonine Kinases; D058571:Vacuolar Sorting Protein VPS15; D000071193:Autophagy-Related Protein 7
references: Mol Biol Cell. 2002 Sep;13(9):3355-68
references: 12221139
references: Mol Cell. 2011 Oct 7;44(1):134-46
references: 21981924
references: Mol Cell Biol. 1988 Nov;8(11):4936-48
references: 3062374
references: Curr Biol. 2007 Sep 18;17(18):1561-7
references: 17683935
references: Science. 1993 Apr 2;260(5104):88-91
references: 8385367
references: J Cell Biol. 2001 Feb 5;152(3):519-30
references: 11157979
references: J Immunol. 2011 Nov 15;187(10):5051-61
references: 22021616
references: Curr Neurol Neurosci Rep. 2003 Jan;3(1):64-9
references: 12507414
references: Nat Cell Biol. 2009 Apr;11(4):385-96
references: 19270696
references: FEBS Lett. 2007 Jul 24;581(18):3396-404
references: 17618624
references: Biochim Biophys Acta. 2009 Apr;1793(4):664-73
references: 18706940
references: J Cell Biol. 2005 May 9;169(3):425-34
references: 15866887
references: Cell Metab. 2009 Dec;10(6):507-15
references: 19945408
references: Nature. 2004 Dec 23;432(7020):1032-6
references: 15525940
references: Proc Biol Sci. 1992 May 22;248(1322):163-9
references: 1352891
references: Nucleic Acids Res. 1999 Oct 1;27(19):e27
references: 10481039
references: Science. 2011 Nov 4;334(6056):678-83
references: 22053050
references: Neuromuscul Disord. 2008 Jul;18(7):521-9
references: 18502640
references: Nat Rev Mol Cell Biol. 2010 May;11(5):329-41
references: 20379207
references: Cell Metab. 2007 Jun;5(6):476-87
references: 17550782
references: EMBO J. 2011 Jul 29;30(16):3242-58
references: 21804531
references: Nucleic Acids Res. 1995 Dec 25;23(24):5080-1
references: 8559668
references: Proc Natl Acad Sci U S A. 2010 Aug 17;107(33):14697-702
references: 20682747
references: Oncogene. 2004 Dec 16;23(58):9314-25
references: 15602573
references: Nat Cell Biol. 2011 Dec 22;14(1):38-45
references: 22193162
references: FEBS Lett. 2010 Apr 2;584(7):1411-6
references: 20132819
references: Nature. 2000 Aug 24;406(6798):906-10
references: 10972294
references: Curr Biol. 2007 Oct 23;17(20):1817-25
references: 17935992
references: Proc Natl Acad Sci U S A. 2005 Oct 4;102(40):14238-43
references: 16176982
references: Traffic. 2010 Apr;11(4):468-78
references: 20059746
references: Autophagy. 2010 Nov;6(8):1078-89
references: 20861693
references: Hum Mol Genet. 2008 Dec 15;17(24):3897-908
references: 18782848
references: Autophagy. 2008 Feb;4(2):185-94
references: 18059170
references: Methods Enzymol. 2009;452:97-118
references: 19200878
references: PLoS One. 2011 Jan 20;6(1):e16358
references: 21283715
references: J Cell Sci. 1999 Dec;112 ( Pt 23):4175-83
references: 10564636
references: Cell Res. 2010 Jul;20(7):748-62
references: 20548331
references: Autophagy. 2007 Sep-Oct;3(5):452-60
references: 17534139
references: Methods Enzymol. 2009;452:247-60
references: 19200887
references: Cell Metab. 2007 Dec;6(6):458-71
references: 18054315
references: FEBS Lett. 2010 Apr 2;584(7):1313-8
references: 20188094
references: Mol Biol Cell. 2004 Mar;15(3):1101-11
references: 14699058
references: Nat Cell Biol. 2009 Apr;11(4):468-76
references: 19270693
references: EMBO J. 1998 Nov 16;17(22):6649-59
references: 9822608
references: Biochem J. 2009 Feb 1;417(3):747-55
references: 18957027
references: Circ Res. 2010 Dec 10;107(12):1470-82
references: 20947830
references: J Cell Biol. 2011 Oct 31;195(3):435-47
references: 22024166
references: J Cell Biol. 1988 Oct;107(4):1369-83
references: 3049619
references: Nat Cell Biol. 2010 Mar;12(3):207-9
references: 20190829
references: J Biol Chem. 2005 Sep 23;280(38):33076-82
references: 16049009
references: Nature. 2000 Aug 24;406(6798):902-6
references: 10972293
references: J Neurosci. 2009 Jul 1;29(26):8506-11
references: 19571141
references: FEBS Lett. 2010 Apr 2;584(7):1287-95
references: 20083114
references: Am J Physiol Endocrinol Metab. 2009 Apr;296(4):E592-602
references: 18765678
references: J Biol Chem. 2000 Aug 11;275(32):24595-600
references: 10807926
references: Nat Rev Mol Cell Biol. 2011 Dec 14;13(1):7-12
references: 22166994
references: Proc Natl Acad Sci U S A. 2012 May 29;109(22):8670-5
references: 22592798
references: Mol Cell. 2012 Mar 9;45(5):629-41
references: 22342342
references: J Cell Biol. 2009 Sep 21;186(6):773-82
references: 19797076
references: Nat Med. 2010 Nov;16(11):1313-20
references: 21037586
references: Exp Cell Res. 2010 Dec 10;316(20):3368-78
references: 20643123
references: J Cell Biol. 2008 May 19;181(4):655-66
references: 18474623
references: Proc Natl Acad Sci U S A. 2012 Feb 7;109(6):2003-8
references: 22308354
references: Nat Rev Mol Cell Biol. 2007 Nov;8(11):931-7
references: 17712358