| First Author | Shen Y | Year | 2020 |
| Journal | FASEB J | Volume | 34 |
| Issue | 5 | Pages | 7144-7159 |
| PubMed ID | 32275117 | Mgi Jnum | J:316350 |
| Mgi Id | MGI:6707256 | Doi | 10.1096/fj.201903073R |
| Citation | Shen Y, et al. (2020) TRAF3 promotes ROS production and pyroptosis by targeting ULK1 ubiquitination in macrophages. FASEB J 34(5):7144-7159 |
| abstractText | Disrupted mitochondrial function and reactive oxygen species (ROS) generation cause cellular damage and oxidative stress-induced macrophage inflammatory cell death. It remains unclear how mitochondrial dysfunction relates to inflammasome activation and pyroptotic cell death. In this study, we demonstrated that tumor necrosis factor receptor-associated factor 3 (TRAF3) regulates mitochondrial ROS production and promotes TLR agonist LPS plus nigericin (LPS/Ng)-induced inflammasome and pyroptosis in mouse primary macrophages and human monocyte THP-1 cells. Co-IP assays confirmed that TRAF3 forms a complex with TRAF2 and cIAP1 and mediates ubiquitin and degradation of Unc-51 like autophagy activating kinase 1 (ULK1). Moreover, knockdown of ULK1 in THP-1 cells significantly promoted LPS/Ng-induced inflammasome by activating caspase 1 and mature IL-1beta. Apoptosis inducing factor (AIF) translocation from mitochondrial to nuclear was observed in ULK1-deficient THP-1 cells under LPS/Ng stimulation, which mediates LPS/Ng-induced cell death in ULK1 deficient macrophages. In conclusion, this study identified a novel role of TRAF3 in regulation of ULK1 ubiquitination and inflammasome signaling and provided molecular mechanisms by which ubiquitination of ULK1 controls mitochondrial ROS production, inflammasome activity, and AIF-dependent pyroptosis. |
