Cutting edge: K63-linked polyubiquitination of NEMO modulates TLR signaling and inflammation in vivo.

Ni CY, Wu ZH, Florence WC, Parekh VV, Arrate MP, Pierce S, Schweitzer B, Van Kaer L, Joyce S, Miyamoto S, Ballard DW, Oltz EM
J Immunol. 2008 180 (11): 7107-11

PMID: 18490708 · PMCID: PMC2601684 · DOI:10.4049/jimmunol.180.11.7107

Transcription factor NF-kappaB controls the expression of multiple genes involved in immunity and inflammation. The initial activation and duration of NF-kappaB signaling is regulated by posttranslational modifications to IkappaB kinase, which earmarks inhibitors of NF-kappaB for degradation. Prior studies suggest that K63-linked ubiquitination of NEMO (NF-kappaB essential modulator), an IkappaB kinase regulatory subunit, is critical for NF-kappaB and MAPK signaling following engagement of Ag receptors. We now demonstrate that NF-kappaB and MAPK pathways are largely unaffected in primary cells from mice harboring a ubiquitination-defective form of NEMO, NEMO-KR. TLR- but not Ag receptor-induced cellular responses are impaired in NEMO-KR mice, which are more resistant to LPS-induced endotoxic shock than wild-type animals. Thus, one function of NEMO ubiquitination is to fine tune innate immune responses under TLR control.

MeSH Terms (14)

Animals Cytokines Hemocyanins I-kappa B Kinase Inflammation Intracellular Signaling Peptides and Proteins Lipopolysaccharides MAP Kinase Signaling System Mice Mitogen-Activated Protein Kinases NF-kappa B Signal Transduction Toll-Like Receptors Ubiquitination

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