title: Cutting edge: K63-linked polyubiquitination of NEMO modulates TLR signaling and inflammation in vivo.
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.
authors.affiliation: Department of Microbiology and Immunology, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Chang-Yuan
authors.initials: CY
authors.lastname: Ni
authors.forename: Zhao-Hui
authors.initials: ZH
authors.lastname: Wu
authors.forename: William C
authors.initials: WC
authors.lastname: Florence
authors.forename: Vrajesh V
authors.initials: VV
authors.lastname: Parekh
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Arrate
authors.forename: Steven
authors.initials: S
authors.lastname: Pierce
authors.forename: Brock
authors.initials: B
authors.lastname: Schweitzer
authors.forename: Luc
authors.initials: L
authors.lastname: Van Kaer
authors.forename: Sebastian
authors.initials: S
authors.lastname: Joyce
authors.forename: Shigeki
authors.initials: S
authors.lastname: Miyamoto
authors.forename: Dean W
authors.initials: DW
authors.lastname: Ballard
authors.forename: Eugene M
authors.initials: EM
authors.lastname: Oltz
mesh_terms: D000818:Animals; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D006433:Hemocyanins / Q000276:immunology; D051550:I-kappa B Kinase / Q000378:metabolism*; D007249:Inflammation / Q000276:immunology / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000276:immunology; D020935:MAP Kinase Signaling System; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; C514981:NEMO protein, mouse; D016328:NF-kappa B; D051193:Toll-Like Receptors; D006433:Hemocyanins; D051550:I-kappa B Kinase; D020928:Mitogen-Activated Protein Kinases; C032808:keyhole-limpet hemocyanin