Pnpt1 mediates NLRP3 inflammasome activation by MAVS and metabolic reprogramming in macrophages

Polyribonucleotide nucleotidyltransferase 1 (Pnpt1) plays critical roles in mitochondrial homeostasis by controlling mitochondrial RNA (mt-RNA) processing, trafficking and degradation. Pnpt1 deficiency results in mitochondrial dysfunction that triggers a type I interferon response, suggesting a role...

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Veröffentlicht in:Cellular & molecular immunology 2023-02, Vol.20 (2), p.131-142
Hauptverfasser: Hsu, Chia George, Li, Wenjia, Sowden, Mark, Chávez, Camila Lage, Berk, Bradford C.
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Sprache:eng
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Zusammenfassung:Polyribonucleotide nucleotidyltransferase 1 (Pnpt1) plays critical roles in mitochondrial homeostasis by controlling mitochondrial RNA (mt-RNA) processing, trafficking and degradation. Pnpt1 deficiency results in mitochondrial dysfunction that triggers a type I interferon response, suggesting a role in inflammation. However, the role of Pnpt1 in inflammasome activation remains largely unknown. In this study, we generated myeloid-specific Pnpt1-knockout mice and demonstrated that Pnpt1 depletion enhanced interleukin-1 beta (IL-1β) and interleukin-18 (IL-18) secretion in a mouse sepsis model. Using cultured peritoneal and bone marrow-derived macrophages, we demonstrated that Pnpt1 regulated NLRP3 inflammasome-dependent IL-1β release in response to lipopolysaccharide (LPS), followed by nigericin, ATP or poly (I:C) treatment. Pnpt1 deficiency in macrophages increased glycolysis after LPS administration and mt-reactive oxygen species (mt-ROS) after NLRP3 inflammasome activation. Pnpt1 activation of the inflammasome was dependent on increased glycolysis and the expression of mitochondrial antiviral-signaling protein (MAVS) but not NF-κB signaling. Collectively, these data suggest that Pnpt1 is an important mediator of inflammation, as shown by activation of the NLRP3 inflammasome in murine sepsis and cultured macrophages.
ISSN:2042-0226
1672-7681
2042-0226
DOI:10.1038/s41423-022-00962-2