Zfand5 terminates TLR3/4 signaling and necroptosis by targeting TRIF to the proteasome for degradation.

Toll-like receptors (TLRs) are central to host defense and tissue repair, yet dysregulated TLR signaling contributes to inflammatory and autoimmune diseases. Although core TLR pathways have been defined, the mechanisms that terminate receptor signaling and restore immune homeostasis remain incompletely understood. Here, we identify the zinc finger protein Zfand5, a known proteasomal shuttling factor, as a selective negative regulator of TLR3- and TLR4-mediated inflammatory responses. Zfand5-deficient mice exhibit exacerbated sepsis and heightened cytokine production following TLR3/4 stimulation. Mechanistically, Zfand5 facilitates the proteasomal degradation of the adaptor protein TIR-domain-containing adapter-inducing interferon-β (TRIF) by bridging polyubiquitinated TRIF to the proteasome, thereby terminating downstream pro-inflammatory and type I interferon signaling. Loss of Zfand5 also enhances TRIF-dependent necroptosis upon TLR3/4 activation, further amplifying inflammation. These findings reveal an essential and previously unrecognized role for Zfand5 in regulating TRIF turnover and maintaining immune balance during innate immune responses.