Kawagoe T*, Takeuchi O*, Takabatake Y, Kato H, Isaka Y, Tsujimura T, Akira S.
TANK is a negative regulator of Toll-like receptor signaling and is critical for the prevention of autoimmune nephritis.
Nat Immunol. 2009 Sep;10(9):965-72.
* Contributed equally.
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-kB. 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.