USP25 promotes endotoxin tolerance via suppressing K48-linked ubiquitination and degradation of TRAF3 in Kupffer cells.
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.
Mesh Terms:
Animals, Endotoxins, Gene Knockdown Techniques, Immune Tolerance, Kupffer Cells, Lentivirus, MAP Kinase Kinase 4, Male, Mice, Proteolysis, TNF Receptor-Associated Factor 3, Ubiquitin Thiolesterase, Ubiquitination, p38 Mitogen-Activated Protein Kinases
Animals, Endotoxins, Gene Knockdown Techniques, Immune Tolerance, Kupffer Cells, Lentivirus, MAP Kinase Kinase 4, Male, Mice, Proteolysis, TNF Receptor-Associated Factor 3, Ubiquitin Thiolesterase, Ubiquitination, p38 Mitogen-Activated Protein Kinases
Mol. Immunol.
Date: Dec. 01, 2018
PubMed ID: 30579117
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