Site-specific monoubiquitination of IκB kinase IKKβ regulates its phosphorylation and persistent activation

被引:28
作者
Carter, RS [1 ]
Pennington, KN [1 ]
Arrate, P [1 ]
Oltz, EM [1 ]
Ballard, DW [1 ]
机构
[1] Vanderbilt Univ, Sch Med, Dept Microbiol & Immunol, Nashville, TN 37232 USA
关键词
D O I
10.1074/jbc.M508656200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Transcription factor NF-kappa B governs the expression of multiple genes involved in cell growth, immunity, and inflammation. Nuclear translocation of NF-kappa B is regulated from the cytoplasm by I kappa B kinase-beta (IKK beta), which earmarks inhibitors of NF-kappa B for polyubiquination and proteasome-mediated degradation. Activation of IKK beta is contingent upon signal-induced phosphorylation of its T loop at Ser-177/Ser-181. T loop phosphorylation also renders IKK beta a substrate for monoubiquitination in cells exposed to chronic activating cues, such as the Tax oncoprotein or sustained signaling through proinflammatory cytokine receptors. Here we provide evidence that the T loop-proximal residue Lys-163 in IKK beta serves as a major site for signal-induced monoubiquitination with significant regulatory potential. Conservative replacement of Lys-163 with Arg yielded a monoubiquitination-defective mutant of IKK beta that retains kinase activity in Tax-expressing cells but is impaired for activation mediated by chronic signaling from the type 1 receptor for tumor necrosis factor-alpha. Phosphopeptide mapping experiments revealed that the Lys-163 3 Arg mutation also interferes with proper in vivo but not in vitro phosphorylation of cytokine-responsive serine residues located in the distal C-terminal region of IKK beta. Taken together, these data indicate that chronic phosphorylation of IKK beta at Ser-177/Ser-181 leads to monoubiquitin attachment at nearby Lys-163, which in turn modulates the phosphorylation status of IKK beta at select C-terminal serines. This mechanism for post-translational cross-talk may play an important role in the control of IKK beta signaling during chronic inflammation.
引用
收藏
页码:43272 / 43279
页数:8
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