Ubiquitin-specific Protease 4 Mitigates Toll-like/Interleukin-1 Receptor Signaling and Regulates Innate Immune Activation

Background: The TRAF6-mediated Toll-like receptor (TLR)/IL-1 receptor (IL-1R) pathway is essential for innate immune responses and immune homeostasis.Results: USP4 deubiquitinates Lys-63-linked polyubiquitination of TRAF6 and thereby prevents the TLR/IL-1R-induced activation of NF-kappa B and AP-1 transcription factors and subsequent proinflammatory responses.Conclusion: USP4 plays an essential role in the negative regulation of the TLR/IL-1R signaling-mediated innate immune response.Significance: USP4 is an attractive new therapeutic target for modulation of innate immune responses.