E3 ligase RNF99 negatively regulates TLR-mediated inflammatory immune response via K48-linked ubiquitination of TAB2

Innate immunity is the first line to defend against pathogenic microorganisms, and Toll-like receptor (TLR)-mediated inflammatory responses are an essential component of innate immunity. However, the regulatory mechanisms of TLRs in innate immunity remain unperfected. We found that the expression of E3 ligase Ring finger protein 99 (RNF99) decreased significantly in peripheral blood monocytes from patients infected with Gram negative bacteria (G - ) and macrophages stimulated by TLRs ligands, indicating the role of RNF99. We also demonstrated for the first time, the protective role of RNF99 against LPS-induced septic shock and dextran sodium sulfate (DSS)-induced colitis using RNF99 knockout mice (RNF99 -/- ) and bone marrow-transplanted mice. In vitro experiments revealed that RNF99 deficiency significantly promoted TLR-mediated inflammatory cytokine…