title: WASH inhibits autophagy through suppression of Beclin 1 ubiquitination.
abstract: Autophagy degrades cytoplasmic proteins and organelles to recycle cellular components that are required for cell survival and tissue homeostasis. However, it is not clear how autophagy is regulated in mammalian cells. WASH (Wiskott-Aldrich syndrome protein (WASP) and SCAR homologue) plays an essential role in endosomal sorting through facilitating tubule fission via Arp2/3 activation. Here, we demonstrate a novel function of WASH in modulation of autophagy. We show that WASH deficiency causes early embryonic lethality and extensive autophagy of mouse embryos. WASH inhibits vacuolar protein sorting (Vps)34 kinase activity and autophagy induction. We identified that WASH is a new interactor of Beclin 1. Beclin 1 is ubiquitinated at lysine 437 through lysine 63 linkage in cells undergoing autophagy. Ambra1 is an E3 ligase for lysine 63-linked ubiquitination of Beclin 1 that is required for starvation-induced autophagy. The lysine 437 ubiquitination of Beclin 1 enhances the association with Vps34 to promote Vps34 activity. WASH can suppress Beclin 1 ubiquitination to inactivate Vps34 activity leading to suppression of autophagy.
authors: Key Laboratory of Infection and Immunity of CAS, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
authors: Pengyan
authors: P
authors: Xia
authors: Shuo
authors: S
authors: Wang
authors: Ying
authors: Y
authors: Du
authors: Zhenao
authors: Z
authors: Zhao
authors: Lei
authors: L
authors: Shi
authors: Lei
authors: L
authors: Sun
authors: Guanling
authors: G
authors: Huang
authors: Buqing
authors: B
authors: Ye
authors: Chong
authors: C
authors: Li
authors: Zhonghua
authors: Z
authors: Dai
authors: Ning
authors: N
authors: Hou
authors: Xuan
authors: X
authors: Cheng
authors: Qingyuan
authors: Q
authors: Sun
authors: Lei
authors: L
authors: Li
authors: Xiao
authors: X
authors: Yang
authors: Zusen
authors: Z
authors: Fan
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001343:Autophagy / Q000235:genetics*; D000071186:Beclin-1; D002478:Cells, Cultured; D058546:Class III Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015536:Down-Regulation / Q000235:genetics; D020964:Embryo Loss / Q000235:genetics*; D004622:Embryo, Mammalian / Q000378:metabolism; D005804:Genes, Lethal / Q000502:physiology; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics / Q000502:physiology*; D054875:Ubiquitination / Q000235:genetics*; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D008565:Membrane Proteins; D008840:Microfilament Proteins; D033921:Vesicular Transport Proteins; C549919:WASH protein, human; C577014:WASH protein, mouse; D058546:Class III Phosphatidylinositol 3-Kinases
references: Dev Cell. 2009 Nov;17(5):699-711
references: 19922874
references: J Biol Chem. 2010 May 28;285(22):16951-7
references: 20308062
references: J Cell Biol. 2011 Jan 10;192(1):17-27
references: 21220506
references: Cell. 2011 Jan 7;144(1):41-54
references: 21215368
references: Cell. 2011 Nov 11;147(4):728-41
references: 22078875
references: Dev Cell. 2011 Mar 15;20(3):291-302
references: 21397841
references: Science. 2004 Nov 5;306(5698):990-5
references: 15528435
references: Nat Cell Biol. 2006 Jul;8(7):688-99
references: 16799551
references: EMBO Rep. 2001 Apr;2(4):330-5
references: 11306555
references: Science. 2010 Mar 26;327(5973):1638-42
references: 20339072
references: Proc Natl Acad Sci U S A. 2010 Jun 8;107(23):10442-7
references: 20498093
references: Mol Cell. 2006 Sep 1;23(5):709-21
references: 16949367
references: Science. 2004 Feb 27;303(5662):1371-4
references: 14739464
references: J Cell Sci. 1996 Dec;109 ( Pt 12):2905-14
references: 9013338
references: Nature. 2007 Jun 28;447(7148):1121-5
references: 17589504
references: Cell. 2010 Dec 10;143(6):951-65
references: 21145461
references: Dev Cell. 2009 Nov;17(5):712-23
references: 19922875
references: FEBS Lett. 2007 Jul 24;581(18):3396-404
references: 17618624
references: Biochem J. 2012 Jan 1;441(1):399-406
references: 21936852
references: Sci Signal. 2010 May 25;3(123):ra42
references: 20501938
references: Cell. 2011 Nov 23;147(5):1024-39
references: 22118460
references: Science. 2004 Jun 4;304(5676):1500-2
references: 15131264
references: Nature. 2004 Dec 23;432(7020):1032-6
references: 15525940
references: J Cell Sci. 2006 Jan 15;119(Pt 2):259-70
references: 16390869
references: J Biol Chem. 2007 Apr 20;282(16):12104-11
references: 17308307
references: Nat Rev Mol Cell Biol. 2009 Jul;10(7):458-67
references: 19491929
references: Science. 2011 Jan 28;331(6016):456-61
references: 21205641
references: Nature. 2010 Jun 17;465(7300):942-6
references: 20526321
references: Cell. 2005 Sep 23;122(6):927-39
references: 16179260
references: Trends Cell Biol. 2010 Jun;20(6):355-62
references: 20356743
references: Mol Biol Cell. 2008 Nov;19(11):4651-9
references: 18768752
references: Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):15077-82
references: 14657337
references: Nat Cell Biol. 2009 Apr;11(4):468-76
references: 19270693
references: Mol Biol Cell. 2008 Dec;19(12):5360-72
references: 18843052
references: Cell. 2009 Jun 12;137(6):1062-75
references: 19524509
references: EMBO Rep. 2009 Mar;10(3):285-92
references: 19180116
references: J Biol Chem. 2003 Sep 19;278(38):36410-7
references: 12829704
references: Mol Cell. 2011 Apr 8;42(1):23-35
references: 21353614
references: PLoS Genet. 2007 Dec;3(12):e237
references: 18159949
references: Cell. 2011 Jan 21;144(2):253-67
references: 21241894
references: Nat Cell Biol. 2007 Oct;9(10):1142-51
references: 17891140
references: Cell. 2003 Mar 7;112(5):659-72
references: 12628186
references: Annu Rev Biochem. 2011;80:125-56
references: 21548784
references: EMBO J. 2000 Nov 1;19(21):5720-8
references: 11060023
references: Mol Cell. 2010 May 28;38(4):500-11
references: 20513426
references: Nat Cell Biol. 2009 Apr;11(4):385-96
references: 19270696
references: Cell. 2010 Jun 25;141(7):1146-58
references: 20541250