TANK is a negative regulator of Toll-like receptor signaling and critical for preventing autoimmune nephritis

The intensity and duration of immune responses are controlled by multiple proteins that modulate Toll-like receptor (TLR) signaling. TRAF family member-associated NF-κB activator (TANK) has been implicated in positive regulation of interferon-regulatory factor-3 as well as NF-κB. 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 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 rescued by antibiotic treatment or the absence of interleukin (IL)-6 or MyD88. These results demonstrate that constitutive TLR signaling by intestinal commensal microflora is suppressed by TANK.