期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 21, 期 14, 页码 -出版社
MDPI
DOI: 10.3390/ijms21145104
关键词
Cbl; NLRP3; inflammasome; glycolysis; GLUT1
资金
- Ministry of Science and Technology, Taiwan [MOST 108-2320-B-715-001, MOST 106-2811-B-182-015]
- Mackay Medical College, Taiwan [1071B26, 1081B16]
- Mackay Memorial Hospital, Taiwan [MMH-MM-10802, 10904]
- Tri-Service General Hospital, Taiwan [TSGH-E-109240, TSGH-PH-E 109013]
Activation of the nod-like receptor 3 (NLRP3) inflammasomes is crucial for immune defense, but improper and excessive activation causes inflammatory diseases. We previously reported that Cbl plays a pivotal role in suppressing NLRP3 inflammasome activation by inhibiting Pyk2-mediated apoptosis-associated speck-like protein containing a CARD (ASC) oligomerization. Here, we showed that Cbl dampened NLRP3 inflammasome activation by inhibiting glycolysis, as demonstrated with Cbl knockout cells and treatment with the Cbl inhibitor hydrocotarnine. We revealed that the inhibition of Cbl promoted caspase-1 cleavage and interleukin (IL)-1 beta secretion through a glycolysis-dependent mechanism. Inhibiting Cbl increased cellular glucose uptake, glycolytic capacity, and mitochondrial oxidative phosphorylation capacity. Upon NLRP3 inflammasome activation, inhibiting Cbl increased glycolysis-dependent activation of mitochondrial respiration and increased the production of reactive oxygen species, which contributes to NLRP3 inflammasome activation and IL-1 beta secretion. Mechanistically, inhibiting Cbl increased surface expression of glucose transporter 1 (GLUT1) protein through post-transcriptional regulation, which increased cellular glucose uptake and consequently raised glycolytic capacity, and in turn enhanced NLRP3 inflammasome activation. Together, our findings provide new insights into the role of Cbl in NLRP3 inflammasome regulation through GLUT1 downregulation. We also show that a novel Cbl inhibitor, hydrocortanine, increased NLRP3 inflammasome activity via its effect on glycolysis.
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