MyD88 and Trif target Beclin 1 to trigger autophagy in macrophages.
The Toll-like receptors (TLR) play an instructive role in innate and adaptive immunity by recognizing specific molecular patterns from pathogens. Autophagy removes intracellular pathogens and participates in antigen presentation. Here, we demonstrate that not only TLR4, but also other TLR family members induce autophagy in macrophages, which is inhibited by MyD88, Trif, or Beclin 1 shRNA expression. MyD88 and Trif co-immunoprecipitate with Beclin 1, a key factor in autophagosome formation. TLR signaling enhances the interaction of MyD88 and Trif with Beclin 1, and reduces the binding of Beclin 1 to Bcl-2. These findings indicate TLR signaling via its adaptor proteins reduces the binding of Beclin 1 to Bcl-2 by recruiting Beclin 1 into the TLR-signaling complex leading to autophagy.
Shi
Chong-Shan
CS
B Cell Molecular Immunology Section, Laboratory of Immunoregulation, NIAID, National Institutes of Health, Bethesda, Maryland 20892, USA. cshi@niaid.nih.gov
Kehrl
John H
JH
D033942:Adaptor Proteins, Vesicular Transport / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001343:Autophagy / Q000502:physiology*; D000071186:Beclin-1; D002460:Cell Line; D005786:Gene Expression Regulation / Q000502:physiology; D007113:Immunity, Innate / Q000502:physiology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D011506:Proteins / Q000276:immunology / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000276:immunology / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D015398:Signal Transduction / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism*
D033942:Adaptor Proteins, Vesicular Transport; D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; D053594:Myeloid Differentiation Factor 88; D011506:Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051197:Toll-Like Receptor 4; C115010:Becn1 protein, mouse; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C493487:Tlr4 protein, mouse; C052617:Bcl2 protein, mouse
Nat Rev Immunol. 2007 Mar;7(3):179-90
17318230
J Biol Chem. 2005 Nov 25;280(47):38969-75
16176925
Nat Rev Immunol. 2007 May;7(5):353-64
17457343
Nat Immunol. 2006 Oct;7(10):1074-81
16964262
EMBO J. 2007 May 16;26(10):2527-39
17446862
J Immunol. 2003 Nov 1;171(9):4758-64
14568952
Nature. 2006 Apr 6;440(7085):808-12
16489357
Science. 2004 Nov 5;306(5698):990-5
15528435
J Immunol. 2002 Jun 15;168(12):5997-6001
12055206
Cell. 2005 Sep 23;122(6):927-39
16179260
Cell. 2006 Feb 24;124(4):783-801
16497588
Trends Immunol. 2005 Oct;26(10):523-8
16099218
Cell Death Differ. 2006 May;13(5):816-25
16410796
Mol Cell. 1998 Aug;2(2):253-8
9734363
J Clin Invest. 2006 Sep;116(9):2366-77
16955139
Nat Immunol. 2001 Aug;2(8):675-80
11477402
Cell. 2004 Dec 17;119(6):753-66
15607973
Immunity. 2007 Jan;26(1):79-92
17182262
J Immunol. 2002 Dec 15;169(12):6668-72
12471095
EMBO J. 2008 Apr 9;27(7):1110-21
18337753
EMBO Rep. 2001 Apr;2(4):330-5
11306555
Immunity. 2007 Jul;27(1):135-44
17658277
Immunity. 2007 Jul;27(1):11-21
17663981
Nat Rev Immunol. 2004 Jul;4(7):499-511
15229469
Nat Cell Biol. 2007 Oct;9(10):1102-9
17909521
Nat Med. 2008 Apr;14(4):399-406
18327267
Nat Rev Immunol. 2006 Dec;6(12):895-906
17110955
Nat Rev Immunol. 2007 Oct;7(10):767-77
17767194
EMBO J. 2000 Nov 1;19(21):5720-8
11060023