TANK is a negative regulator of Toll-like receptor signaling and is critical for the prevention of autoimmune nephritis.
The intensity and duration of immune responses are controlled by many proteins that modulate Toll-like receptor (TLR) signaling. TANK has been linked to positive regulation of the transcription factors IRF3 and NF-kappaB. Here we demonstrate that TANK is not involved in interferon responses and is a negative regulator of proinflammatory cytokine production induced by TLR signaling. TLR-induced polyubiquitination of the ubiquitin ligase TRAF6 was upregulated in Tank(-/-) macrophages. Notably, Tank(-/-) mice spontaneously developed fatal glomerulonephritis owing to deposition of immune complexes. Autoantibody production in Tank(-/-) mice was abrogated by antibiotic treatment or the absence of interleukin 6 (IL-6) or the adaptor MyD88. Our results demonstrate that constitutive TLR signaling by intestinal commensal microflora is suppressed by TANK.
Kawagoe
Tatsukata
T
Laboratory of Host Defense, World Premier International Immunology Frontier Research Center, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
Takeuchi
Osamu
O
Takabatake
Yoshitsugu
Y
Kato
Hiroki
H
Isaka
Yoshitaka
Y
Tsujimura
Tohru
T
Akira
Shizuo
S
D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000818:Animals; D001327:Autoimmune Diseases / Q000517:prevention & control*; D015551:Autoimmunity; D019013:CD40 Antigens / Q000502:physiology; D005260:Female; D005921:Glomerulonephritis / Q000517:prevention & control*; D007422:Intestines / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology; D011947:Receptors, Antigen, B-Cell / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D051193:Toll-Like Receptors / Q000502:physiology*; D025801:Ubiquitin / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D019013:CD40 Antigens; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D011947:Receptors, Antigen, B-Cell; D048029:TNF Receptor-Associated Factor 6; C100814:Tank protein, mouse; D051193:Toll-Like Receptors; D025801:Ubiquitin