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Cutting Edge: K63-Linked Polyubiquitination of NEMO Modulates TLR Signaling and Inflammation In Vivo

2008; American Association of Immunologists; Volume: 180; Issue: 11 Linguagem: Inglês

10.4049/jimmunol.180.11.7107

1550-6606

Chang-Yuan Ni, Zhao‐Hui Wu, William C. Florence, Vrajesh V. Parekh, Maria P. Arrate, Steven Pierce, Brock L. Schweitzer, Luc Van Kaer, Sebastian Joyce, Shigeki Miyamoto, Dean W. Ballard, Eugene M. Oltz,

Immune cells in cancer

Abstract Transcription factor NF-κB controls the expression of multiple genes involved in immunity and inflammation. The initial activation and duration of NF-κB signaling is regulated by posttranslational modifications to IκB kinase, which earmarks inhibitors of NF-κB for degradation. Prior studies suggest that K63-linked ubiquitination of NEMO (NF-κB essential modulator), an IκB kinase regulatory subunit, is critical for NF-κB and MAPK signaling following engagement of Ag receptors. We now demonstrate that NF-κB 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.