Autophagic substrate clearance requires activity of the syntaxin-5 SNARE complex.
Autophagy is a lysosome-dependent cellular catabolic mechanism that mediates the turnover of intracellular organelles and long-lived proteins. Reduced autophagic activity has been shown to lead to the accumulation of misfolded proteins in neurons and might be involved in chronic neurodegenerative diseases. Here, we uncover an essential role for the syntaxin-5 SNARE complex in autophagy. Using genetic knockdown, we show that the syntaxin-5 SNARE complex regulates the later stages of autophagy after the initial formation of autophagosomes. This SNARE complex acts on autophagy by regulating ER-to-Golgi transport through the secretory pathway, which is essential for the activity of lysosomal proteases such as cathepsins. Depletion of syntaxin-5 complex components results in the accumulation of autophagosomes as a result of lysosomal dysfunction, leading to decreased degradation of autophagic substrates. Our findings provide a novel link between a fundamental process such as intracellular trafficking and human diseases that might be affected by defective biogenesis and/or homeostasis of the autophagosome-lysosome degradation system.
Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Wellcome/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge CB20XY, UK.
Maurizio
M
Renna
Catherine
C
Schaffner
Ashley R
AR
Winslow
Fiona M
FM
Menzies
Andrew A
AA
Peden
R Andres
RA
Floto
David C
DC
Rubinsztein
D033942:Adaptor Proteins, Vesicular Transport; D001343:Autophagy / Q000502:physiology*; D001692:Biological Transport / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000201:enzymology*; D008869:Microtubule-Associated Proteins / Q000502:physiology; D050765:Qa-SNARE Proteins / Q000502:physiology*; D050683:R-SNARE Proteins / Q000502:physiology; D033921:Vesicular Transport Proteins / Q000502:physiology
D033942:Adaptor Proteins, Vesicular Transport; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D050765:Qa-SNARE Proteins; D050683:R-SNARE Proteins; C527528:SCFD1 protein, human; D033921:Vesicular Transport Proteins
J Biol Chem. 1991 Nov 15;266(32):21327-30
1939168
Mol Cell. 2009 Feb 27;33(4):517-27
19250912
Mol Biol Cell. 2010 Mar 15;21(6):1001-10
20089838
Biochim Biophys Acta. 2009 Dec;1793(12):1901-16
19781582
J Med Genet. 1999 Oct;36(10):739-46
10528852
Dev Cell. 2004 Apr;6(4):463-77
15068787
Biochim Biophys Acta. 2005 Jun 30;1744(2):120-44
15893389
EMBO J. 2009 Jul 22;28(14):2006-17
19536132
Autophagy. 2007 May-Jun;3(3):181-206
17224625
Nature. 1996 Jul 18;382(6588):262-5
8717042
Mol Biol Cell. 2010 Oct 1;21(19):3386-95
20685960
PLoS Biol. 2006 Nov;4(12):e423
17132049
Cell. 2010 Jun 25;141(7):1146-58
20541250
Nat Genet. 2000 Jun;25(2):173-6
10835631
Nat Rev Mol Cell Biol. 2006 Sep;7(9):631-43
16912714
Traffic. 2010 Sep;11(9):1191-204
20545907
Nature. 2000 Sep 14;407(6801):153-9
11001046
Nat Cell Biol. 2009 Dec;11(12):1433-7
19898463
J Biol Chem. 2006 Oct 6;281(40):30299-304
16901900
Cell. 1997 Apr 4;89(1):149-58
9094723
J Cell Biol. 2008 Aug 25;182(4):685-701
18725538
Nature. 2008 Feb 28;451(7182):1069-75
18305538
Autophagy. 2009 Aug;5(6):835-46
19550143
Autophagy. 2009 Apr;5(3):307-13
19182529
Autophagy. 2008 Feb;4(2):151-75
18188003
Nature. 2000 Aug 24;406(6798):906-10
10972294
Eur J Immunol. 1995 Feb;25(2):481-7
7875211
Dev Biol. 2003 Jun 15;258(2):291-306
12798289
Mol Cell. 1999 Jan;3(1):11-21
10024875
Biochim Biophys Acta. 1995 Apr 24;1270(2-3):103-36
7727535
Hum Mol Genet. 2008 Jan 15;17(2):170-8
17921520
Autophagy. 2007 Sep-Oct;3(5):452-60
17534139
Proc Natl Acad Sci U S A. 2007 Nov 27;104(48):19023-8
18024584
Nature. 1992 Jan 2;355(6355):33-45
1731198
Nature. 1998 Sep 24;395(6700):347-53
9759724
Hum Mol Genet. 2002 May 1;11(9):1107-17
11978769
Genes Dev. 1999 May 15;13(10):1211-33
10346810
FEBS Lett. 2007 May 22;581(11):2156-61
17382324
Mol Biol Cell. 1999 Feb;10(2):435-53
9950687
Traffic. 2000 Nov;1(11):836-51
11208074
Proc Natl Acad Sci U S A. 1997 Apr 1;94(7):3046-51
9096343
J Biol Chem. 2007 Feb 23;282(8):5641-52
17182613
Traffic. 2008 Apr;9(4):574-87
18182013
Science. 1975 Aug 1;189(4200):347-58
1096303
Cell. 2006 Jul 14;126(1):205-18
16839887
Cell. 1996 Apr 19;85(2):205-15
8612273
Nat Rev Drug Discov. 2007 Apr;6(4):304-12
17396135
J Biol Chem. 1994 Apr 29;269(17):13030-5
8175723
Nature. 1993 Mar 25;362(6418):318-24
8455717
Cell. 1998 Mar 20;92(6):759-72
9529252
J Microsc. 2006 Dec;224(Pt 3):213-32
17210054
Autophagy. 2009 Jul;5(5):585-9
19411822
J Biol Chem. 2007 Aug 3;282(31):22499-512
17535801
Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15781-6
9861047
EMBO J. 2000 Nov 1;19(21):5720-8
11060023
J Biol Chem. 1996 Jul 5;271(27):15866-9
8663406
Curr Opin Cell Biol. 2008 Aug;20(4):401-7
18472412
Nat Rev Mol Cell Biol. 2003 Mar;4(3):181-91
12612637