biostudies-literatureHsu CGNIEHS NIH HHSNHLBI NIH HHS131-142https://www.ebi.ac.uk/biostudies/studies/S-EPMC9886977biostudies-literatureUnknown20(2)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 nigeriCellular & molecular immunologyPnpt1 mediates NLRP3 inflammasome activation by MAVS and metabolic reprogramming in macrophages.PMC9886977R01 HL134910R01 HL140958P30 ES001247Li WChavez CLSowden MBerk BCHsu CGfalsePnpt1 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 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 nigeri2023-01-01T00:00:00Z2023 Feb2026-07-15T02:53:43.193Z2025-04-21T15:56:38.127ZS-EPMC98869773659687410.1038/s41423-022-00962-2