Tumor necrosis factor-alpha induces RelA degradation via ubiquitination at lysine 195 to prevent excessive nuclear factor-kappaB activation.
Ubiquitination-mediated degradation of the RelA subunit of nuclear factor-kappaB (NF-kappaB) is critical for the termination of NF-kappaB activation. However, the precise mechanism for the ubiquitination of RelA is still not fully understood. Here we report that tumor necrosis factor-alpha (TNFalpha) induces RelA polyubiquitination at the lysine 195 residue, and this ubiquitination event is critical for the degradation of RelA and termination of TNFalpha-mediated NF-kappaB activation. Overexpression of a RelA mutant with an arginine substitution for the lysine 195 residue dramatically inhibits RelA polyubiquitination and induces a stronger NF-kappaB activation compared with the wild type. Reconstitution of RelA-deficient mouse embryo fibroblast cells with wild-type RelA or RelA containing a K195R mutation revealed the importance of this site in TNFalpha-mediated RelA polyubiquitination, degradation, and attenuation of NF-kappaB activation. Our finding is the first report that substitution of a key RelA lysine residue with arginine inhibits TNFalpha-induced RelA ubiquitination and enhances TNFalpha-induced NF-kappaB activation.
Fan
Yihui
Y
Department of Pediatrics, Texas Children's Cancer Center, Houston, TX 77030, USA.
Mao
Renfang
R
Zhao
Yanling
Y
Yu
Yang
Y
Sun
Wenjing
W
Song
Ping
P
Shi
Zhongcheng
Z
Zhang
Dekai
D
Yvon
Eric
E
Zhang
Hong
H
Fu
Songbin
S
Yang
Jianhua
J
D019943:Amino Acid Substitution; D000818:Animals; D002460:Cell Line; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D051379:Mice; D020125:Mutation, Missense; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology*; D054875:Ubiquitination / Q000187:drug effects / Q000502:physiology*
D016328:NF-kappa B; C498143:RELA protein, human; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D008239:Lysine
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