USP25 promotes endotoxin tolerance via suppressing K48-linked ubiquitination and degradation of TRAF3 in Kupffer cells
- Mol Immunol. 2019 Feb:106:53-62. doi: 10.1016/j.molimm.2018.12.017.
- 1. Department of Hepatobiliary Surgery, he Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China.
- 2. Department of Anesthesiology, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China.
- 3. Department of Hepatobiliary Surgery, he Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China. Electronic address: [email protected].
- 4. Department of Hepatobiliary Surgery, he Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China. Electronic address: [email protected].
The inhibition of tumor necrosis factor receptor-associated factor 3 (TRAF3) degradation induces endotoxin tolerance (ET) in macrophages. However, the mechanisms leading to TRAF3 inhibition by ET are largely unknown. Here, we found that Ubiquitin-Specific Peptidase 25 (USP25), a deubiquitinating enzyme (DUB), interacted with TRAF3 and stabilized ET in Kupffer cells (KCs). Lentiviral knockdown of USP25 activated K48-linked ubiquitination of TRAF3 and the cytoplasmic translocation of the Myd88-associated multiprotein complex in tolerized KCs. This outcome led to a subsequent activation of Myd88-dependent c-Jun N-terminal kinase (JNK) and p38-mediated downregulation of inflammatory cytokines. The overexpression of TRAF3 attenuated the proinflammatory effects of USP25 knockdown in tolerized KCs. Thus, our findings reveal a novel mechanism of endotoxin-mediated TRAF3 degradation in KCs.