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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. Cutting edge: K63-linked polyubiquitination of NEMO modulates TLR signaling and inflammation in vivo. Journal of Immunology. 180(180). 7107-7111. NIHMSID: NIHMS58993.
Abstract
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.