2. Academic Validation
  3. Cbl Negatively Regulates NLRP3 Inflammasome Activation through GLUT1-Dependent Glycolysis Inhibition

Cbl Negatively Regulates NLRP3 Inflammasome Activation through GLUT1-Dependent Glycolysis Inhibition

  • Int J Mol Sci. 2020 Jul 19;21(14):5104. doi: 10.3390/ijms21145104.
Hsin-Chung Lin 1 2,  Yu-Jen Chen 3 4 5,  Yau-Huei Wei 6,  Yu-Ting Chuang 7,  Su-Heng Hsieh 7,  Jing-Yu Hsieh 7,  Yi-Lin Hsieh 7,  David M Ojcius 8,  Kuo-Yang Huang 9,  I-Che Chung 10,  Sheng-Ning Yuan 10,  Yu-Sun Chang 10,  Lih-Chyang Chen 7
Affiliations

Affiliations

  • 1 Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei 114, Taiwan.
  • 2 Division of Clinical Pathology, Department of Pathology, Tri-Service General Hospital, Taipei 114, Taiwan.
  • 3 Department of Radiation Oncology, MacKay Memorial Hospital, New Taipei City 251, Taiwan.
  • 4 Department of Medical Research, MacKay Memorial Hospital, New Taipei City 251, Taiwan.
  • 5 Department of Nursing, MacKay Junior College of Medicine, Nursing, and Management, Taipei 112, Taiwan.
  • 6 Center for Mitochondrial Medicine and Free Radical Research, Changhua Christian Hospital, Changhua 50046, Taiwan.
  • 7 Department of Medicine, Mackay Medical College, New Taipei City 252, Taiwan.
  • 8 Department of Biomedical Sciences, University of the Pacific, Arthur Dugoni School of Dentistry, San Francisco, CA 94103, USA.
  • 9 Graduate Institute of Pathology and Parasitology, National Defense Medical Center, Taipei 114, Taiwan.
  • 10 Molecular Medicine Research Center, Chang Gung University, Taoyuan 333, Taiwan.
PMID: 32707731 DOI: 10.3390/ijms21145104
Abstract

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)-1β 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-1β 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.

Keywords

Cbl; GLUT1; NLRP3; glycolysis; inflammasome.

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