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.
机构:
Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USAMt Sinai Sch Med, Dept Microbiol, New York, NY 10029 USA
Ng, Sze-Ling
Friedman, Brad A.
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Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USAMt Sinai Sch Med, Dept Microbiol, New York, NY 10029 USA
Friedman, Brad A.
Schmid, Sonja
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Mt Sinai Sch Med, Dept Microbiol, New York, NY 10029 USAMt Sinai Sch Med, Dept Microbiol, New York, NY 10029 USA
Schmid, Sonja
Gertz, Jason
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机构:
HudsonAlpha Inst Biotechnol, Huntsville, AL 35806 USAMt Sinai Sch Med, Dept Microbiol, New York, NY 10029 USA
Gertz, Jason
Myers, Richard M.
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机构:
HudsonAlpha Inst Biotechnol, Huntsville, AL 35806 USAMt Sinai Sch Med, Dept Microbiol, New York, NY 10029 USA
Myers, Richard M.
tenOever, Benjamin R.
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机构:
Mt Sinai Sch Med, Dept Microbiol, New York, NY 10029 USAMt Sinai Sch Med, Dept Microbiol, New York, NY 10029 USA
tenOever, Benjamin R.
Maniatis, Tom
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机构:
Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA
Columbia Univ, Dept Biochem & Mol Biophys, New York, NY 10032 USAMt Sinai Sch Med, Dept Microbiol, New York, NY 10029 USA
机构:
Univ Texas, SW Med Ctr, Howard Hughes Med Inst, Dept Mol Biol, Dallas, TX 75390 USAUniv Texas, SW Med Ctr, Howard Hughes Med Inst, Dept Mol Biol, Dallas, TX 75390 USA
Ea, CK
Deng, L
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Univ Texas, SW Med Ctr, Howard Hughes Med Inst, Dept Mol Biol, Dallas, TX 75390 USAUniv Texas, SW Med Ctr, Howard Hughes Med Inst, Dept Mol Biol, Dallas, TX 75390 USA
Deng, L
Xia, ZP
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Univ Texas, SW Med Ctr, Howard Hughes Med Inst, Dept Mol Biol, Dallas, TX 75390 USAUniv Texas, SW Med Ctr, Howard Hughes Med Inst, Dept Mol Biol, Dallas, TX 75390 USA
Xia, ZP
Pineda, G
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Univ Texas, SW Med Ctr, Howard Hughes Med Inst, Dept Mol Biol, Dallas, TX 75390 USAUniv Texas, SW Med Ctr, Howard Hughes Med Inst, Dept Mol Biol, Dallas, TX 75390 USA
Pineda, G
Chen, ZJJ
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机构:
Univ Texas, SW Med Ctr, Howard Hughes Med Inst, Dept Mol Biol, Dallas, TX 75390 USAUniv Texas, SW Med Ctr, Howard Hughes Med Inst, Dept Mol Biol, Dallas, TX 75390 USA
机构:
Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USAMt Sinai Sch Med, Dept Microbiol, New York, NY 10029 USA
Ng, Sze-Ling
Friedman, Brad A.
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h-index: 0
机构:
Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USAMt Sinai Sch Med, Dept Microbiol, New York, NY 10029 USA
Friedman, Brad A.
Schmid, Sonja
论文数: 0引用数: 0
h-index: 0
机构:
Mt Sinai Sch Med, Dept Microbiol, New York, NY 10029 USAMt Sinai Sch Med, Dept Microbiol, New York, NY 10029 USA
Schmid, Sonja
Gertz, Jason
论文数: 0引用数: 0
h-index: 0
机构:
HudsonAlpha Inst Biotechnol, Huntsville, AL 35806 USAMt Sinai Sch Med, Dept Microbiol, New York, NY 10029 USA
Gertz, Jason
Myers, Richard M.
论文数: 0引用数: 0
h-index: 0
机构:
HudsonAlpha Inst Biotechnol, Huntsville, AL 35806 USAMt Sinai Sch Med, Dept Microbiol, New York, NY 10029 USA
Myers, Richard M.
tenOever, Benjamin R.
论文数: 0引用数: 0
h-index: 0
机构:
Mt Sinai Sch Med, Dept Microbiol, New York, NY 10029 USAMt Sinai Sch Med, Dept Microbiol, New York, NY 10029 USA
tenOever, Benjamin R.
Maniatis, Tom
论文数: 0引用数: 0
h-index: 0
机构:
Harvard Univ, Dept Mol & Cellular Biol, Cambridge, MA 02138 USA
Columbia Univ, Dept Biochem & Mol Biophys, New York, NY 10032 USAMt Sinai Sch Med, Dept Microbiol, New York, NY 10029 USA
机构:
Univ Texas, SW Med Ctr, Howard Hughes Med Inst, Dept Mol Biol, Dallas, TX 75390 USAUniv Texas, SW Med Ctr, Howard Hughes Med Inst, Dept Mol Biol, Dallas, TX 75390 USA
Ea, CK
Deng, L
论文数: 0引用数: 0
h-index: 0
机构:
Univ Texas, SW Med Ctr, Howard Hughes Med Inst, Dept Mol Biol, Dallas, TX 75390 USAUniv Texas, SW Med Ctr, Howard Hughes Med Inst, Dept Mol Biol, Dallas, TX 75390 USA
Deng, L
Xia, ZP
论文数: 0引用数: 0
h-index: 0
机构:
Univ Texas, SW Med Ctr, Howard Hughes Med Inst, Dept Mol Biol, Dallas, TX 75390 USAUniv Texas, SW Med Ctr, Howard Hughes Med Inst, Dept Mol Biol, Dallas, TX 75390 USA
Xia, ZP
Pineda, G
论文数: 0引用数: 0
h-index: 0
机构:
Univ Texas, SW Med Ctr, Howard Hughes Med Inst, Dept Mol Biol, Dallas, TX 75390 USAUniv Texas, SW Med Ctr, Howard Hughes Med Inst, Dept Mol Biol, Dallas, TX 75390 USA
Pineda, G
Chen, ZJJ
论文数: 0引用数: 0
h-index: 0
机构:
Univ Texas, SW Med Ctr, Howard Hughes Med Inst, Dept Mol Biol, Dallas, TX 75390 USAUniv Texas, SW Med Ctr, Howard Hughes Med Inst, Dept Mol Biol, Dallas, TX 75390 USA