Abstract
Abstract Protein ubiquitination plays a critical role in Toll-like receptor (TLR) signaling and innate immunity. Although several E3 ubiquitin ligases have been identified downstream of TLRs, the deubiquitination regulation in innate immunity is poorly understood. Here, we identified ubiquitin-specific protease 25 (USP25) as a novel negative regulator for TLR signaling. Deficiency of USP25 potentiated TLR2- and TLR4-induced activation of NF-kB and MAPKs and pro-inflammatory cytokine expression. Consistently, Usp25-/- mice exhibited increased susceptibility to LPS-induced septic shock than the control littermates. USP25 was found recruited to the TLR4 signaling complex and associated with TRAF3 and TRAF6 after LPS stimulation. Notably, USP25 specifically removed cIAP2-induced K48-linked ubiquitin conjugation of TRAF3 and loss of USP25 resulted in enhanced K48-linked ubiquitination and accelerated degradation of TRAF3 after TLR2/4 activation. Our findings thus identify USP25 as a novel, critical negative regulator in innate immunity via regulating TRAF3 degradation during TLR2/4 activation.
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