Lysine 63-linked polyubiquitination of TAK1 at lysine 158 is required for tumor necrosis factor alpha- and interleukin-1beta-induced IKK/NF-kappaB and JNK/AP-1 activation.
Transforming growth factor-beta-activated kinase 1 (TAK1) plays an essential role in the tumor necrosis factor alpha (TNFalpha)- and interleukin-1beta (IL-1beta)-induced IkappaB kinase (IKK)/nuclear factor-kappaB (NF-kappaB) and c-Jun N-terminal kinase (JNK)/activator protein 1 (AP-1) activation. Here we report that TNFalpha and IL-1beta induce Lys(63)-linked TAK1 polyubiquitination at the Lys(158) residue within the kinase domain. Tumor necrosis factor receptor-associated factors 2 and 6 (TRAF2 and -6) act as the ubiquitin E3 ligases to mediate Lys(63)-linked TAK1 polyubiquitination at the Lys(158) residue in vivo and in vitro. Lys(63)-linked TAK1 polyubiquitination at the Lys(158) residue is required for TAK1-mediated IKK complex recruitment. Reconstitution of TAK1-deficient mouse embryo fibroblast cells with TAK1 wild type or a TAK1 mutant containing a K158R mutation revealed the importance of this site in TNFalpha and IL-1beta-mediated IKK/NF-kappaB and JNK/AP-1 activation as well as IL-6 gene expression. Our findings demonstrate that Lys(63)-linked polyubiquitination of TAK1 at Lys(158) is essential for its own kinase activation and its ability to mediate its downstream signal transduction pathways in response to TNFalpha and IL-1beta stimulation.
Fan
Yihui
Y
Laboratory of Medical Genetics, Harbin Medical University, Harbin 150081, China.
Yu
Yang
Y
Shi
Yi
Y
Sun
Wenjing
W
Xie
Min
M
Ge
Ningling
N
Mao
Renfang
R
Chang
Alex
A
Xu
Gufeng
G
Schneider
Michael D
MD
Zhang
Hong
H
Fu
Songbin
S
Qin
Jun
J
Yang
Jianhua
J
D019943:Amino Acid Substitution; D000818:Animals; D002460:Cell Line; D004622:Embryo, Mammalian / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism* / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D008239:Lysine / Q000235:genetics / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008817:Mice, Mutant Strains; D020125:Mutation, Missense; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects / Q000502:physiology*; D000099151:MAP Kinase Kinase Kinase 7
D051550:I-kappa B Kinase; D053583:Interleukin-1beta; D015850:Interleukin-6; D048031:JNK Mitogen-Activated Protein Kinases; D008239:Lysine; D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D047992:TNF Receptor-Associated Factor 2; D048029:TNF Receptor-Associated Factor 6; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D044767:Ubiquitin-Protein Ligases; D000099151:MAP Kinase Kinase Kinase 7; C508600:IL6 protein, human