Cutting edge: K63-linked polyubiquitination of NEMO modulates TLR signaling and inflammation in vivo.
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.
Ni
Chang-Yuan
CY
Department of Microbiology and Immunology, Vanderbilt University, Nashville, TN 37232, USA.
Wu
Zhao-Hui
ZH
Florence
William C
WC
Parekh
Vrajesh V
VV
Arrate
Maria Pia
MP
Pierce
Steven
S
Schweitzer
Brock
B
Van Kaer
Luc
L
Joyce
Sebastian
S
Miyamoto
Shigeki
S
Ballard
Dean W
DW
Oltz
Eugene M
EM
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
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