期刊
CELL DEATH & DISEASE
卷 13, 期 1, 页码 -出版社
SPRINGERNATURE
DOI: 10.1038/s41419-022-04539-9
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资金
- Natural Science Foundation of Hebei Province [H2019201259, H2021201028]
- Hebei Province Foundation for the Returned Overseas Scholars [C20200305]
- CAMS Innovation Fund for Medical Sciences [2019-I2M-5-055]
- Government Foundation of Clinical Medicine Talents Training Program of Hebei Province [361007]
- Medical Science Foundation of Hebei University [2020A09]
- Outstanding Youth Scientific Research and Innovation Team (Science and Technology) Project of Hebei University [2020-8]
- Hospital fund of Affiliated Hospital of Hebei University [2019Z002]
- Hebei University graduate innovation funding project [HBU2021ss038]
TFG plays an essential role in LPS/Ng-induced pyroptotic cell death by regulating the stability of ULK1.
TRK-fused gene (TFG) is known to be involved in protein secretion and plays essential roles in an antiviral innate immune response. However, its function in LPS-induced inflammation and pyroptotic cell death is still unknown. Here, we reported that TFG promotes the stabilization of Unc-51 like autophagy activating kinase (ULK1) and participates in LPS plus nigericin (Ng) induced pyroptotic cell death. Our results showed that TFG-deficient THP-1 macrophages exhibit higher mitochondrial ROS production. LPS/Ng stimulation triggers a much higher level of ROS and induces pyroptotic cell death. ULK1 undergoes a rapid turnover in TFG-deficient THP-1 cells. TFG forms complex with an E3 ligase, tumor necrosis factor receptor-associated factor 3 (TRAF3), and stabilizes ULK1 via disturbing ULK1-TRAF3 interaction. Knockdown of TFG facilitates the interaction of ULK1 with TRAF3 and subsequent K48-linked ULK1 ubiquitination and proteasome degradation. Rescue of ULK1 expression blocks LPS/Ng-induced cell death in TFG-deficient THP-1 macrophages. Taken together, TFG plays an essential role in LPS/Ng-induced pyroptotic cell death via regulating K48-linked ULK1 ubiquitination in macrophages.
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