TAK1 regulates caspase 8 activation and necroptotic signaling via multiple cell death checkpoints.
Necroptosis has emerged as a new form of programmed cell death implicated in a number of pathological conditions such as ischemic injury, neurodegenerative disease, and viral infection. Recent studies indicate that TGFβ-activated kinase 1 (TAK1) is nodal regulator of necroptotic cell death, although the underlying molecular regulatory mechanisms are not well defined. Here we reported that TAK1 regulates necroptotic signaling as well as caspase 8-mediated apoptotic signaling through both NFκB-dependent and -independent mechanisms. Inhibition of TAK1 promoted TNFα-induced cell death through the induction of RIP1 phosphorylation/activation and necrosome formation. Further, inhibition of TAK1 triggered two caspase 8 activation pathways through the induction of RIP1-FADD-caspase 8 complex as well as FLIP cleavage/degradation. Mechanistically, our data uncovered an essential role for the adaptor protein TNF receptor-associated protein with death domain (TRADD) in caspase 8 activation and necrosome formation triggered by TAK1 inhibition. Moreover, ablation of the deubiqutinase CYLD prevented both apoptotic and necroptotic signaling induced by TAK1 inhibition. Finally, blocking the ubiquitin-proteasome pathway prevented the degradation of key pro-survival signaling proteins and necrosome formation. Thus, we identified new regulatory mechanisms underlying the critical role of TAK1 in cell survival through regulation of multiple cell death checkpoints. Targeting key components of the necroptotic pathway (e.g., TRADD and CYLD) and the ubiquitin-proteasome pathway may represent novel therapeutic strategies for pathological conditions driven by necroptosis.
Department of Physiology and Biophysics, University of Washington, Seattle 98195, WA, USA.
Xiaoyun
X
Guo
Department of Physiology and Biophysics, University of Washington, Seattle 98195, WA, USA.
Haifeng
H
Yin
Department of Physiology and Biophysics, University of Washington, Seattle 98195, WA, USA.
Yi
Y
Chen
Department of Physiology and Biophysics, University of Washington, Seattle 98195, WA, USA.
Lei
L
Li
Department of Physiology and Biophysics, University of Washington, Seattle 98195, WA, USA.
Jing
J
Li
Department of Physiology and Biophysics, University of Washington, Seattle 98195, WA, USA.
Qinghang
Q
Liu
D000818:Animals; D017209:Apoptosis; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism*; D059447:Cell Cycle Checkpoints; D003546:Cysteine Endopeptidases / Q000378:metabolism; D000074749:Deubiquitinating Enzyme CYLD; D004789:Enzyme Activation; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009336:Necrosis; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D015398:Signal Transduction; D053199:TNF Receptor-Associated Death Domain Protein / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D053181:Caspase 8; D003546:Cysteine Endopeptidases; D000074749:Deubiquitinating Enzyme CYLD; D053200:Fas-Associated Death Domain Protein; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D046988:Proteasome Endopeptidase Complex; D053199:TNF Receptor-Associated Death Domain Protein; D025801:Ubiquitin; D000099151:MAP Kinase Kinase Kinase 7; C511601:CYLD protein, mouse
Cell. 2009 Jun 12;137(6):1112-23
19524513
Mol Cell Biol. 2013 Feb;33(3):582-95
23166301
Cell Rep. 2013 Nov 27;5(4):878-85
24268776
Mol Cell Biol. 2006 May;26(10):3785-97
16648474
Annu Rev Cell Dev Biol. 2014;30:337-56
25150011
Cell Death Dis. 2011 Nov 17;2:e230
22089168
Nat Immunol. 2008 Sep;9(9):1037-46
18641654
J Biol Chem. 2003 Dec 19;278(51):51613-21
14532286
Science. 1995 Dec 22;270(5244):2008-11
8533096
Cell Death Differ. 2011 Apr;18(4):656-65
21052097
Cell Death Differ. 2012 Jan;19(1):75-86
22075985
Cell. 2011 Apr 1;145(1):92-103
21458669
Proc Natl Acad Sci U S A. 2010 Jan 12;107(2):844-9
20080763
PLoS One. 2013 Oct 02;8(10 ):e76841
24098568
Mol Cell Biol. 2001 Aug;21(16):5299-305
11463813
Nat Rev Mol Cell Biol. 2008 May;9(5):378-90
18414491
Mol Cell Biol. 2006 May;26(9):3505-13
16611992
Cell Death Differ. 2013 Oct;20(10 ):1381-92
23892367
Circulation. 2014 Dec 9;130(24):2162-72
25278099
J Exp Med. 2007 Jun 11;204(6):1475-85
17548520
Curr Biol. 2007 Mar 6;17(5):418-24
17306544
J Biol Chem. 2008 Sep 19;283(38):26161-8
18606807
Mol Cell. 2008 Jun 20;30(6):689-700
18570872
J Biol Chem. 2003 May 16;278(20):18485-90
12624112
Nature. 2002 Jul 11;418(6894):191-5
12110890
PLoS One. 2010 Jan 08;5(1):e8620
20062539
Cell. 1996 Jan 26;84(2):299-308
8565075
J Cell Biol. 2014 Feb 17;204(4):607-23
24535827
Cell. 2009 Jun 12;137(6):1100-11
19524512
Nat Cell Biol. 2009 Feb;11(2):154-61
19136967
Cell. 2003 Jul 25;114(2):181-90
12887920
Science. 2009 Jul 17;325(5938):332-6
19498109
Nat Chem Biol. 2008 May;4(5):313-21
18408713
J Immunol. 2008 Jul 15;181(2):1143-52
18606667
Circ Res. 2012 Apr 13;110(8):1077-86
22403241
Biochim Biophys Acta. 2013 Dec;1833(12):3448-59
23770045
PLoS One. 2011;6(10):e26069
22016814
Cell. 2008 May 16;133(4):693-703
18485876
Cell Death Differ. 2012 Jan;19(1):107-20
21760595
J Biol Chem. 2004 Aug 6;279(32):33185-91
15175328