biostudies-literatureHortle EKenyon Family Inflammation AwardNSW Health Early-Mid Career Fellowships SchemeUniversity of Sydney FellowshipCentenary Institute Booster GrantAustralian National Health and Medical Research Councile202201476https://www.ebi.ac.uk/biostudies/studies/S-EPMC9107790biostudies-literatureUnknown5(9)Pathogenic mycobacteria inhibit inflammasome activation to establish infection. Although it is known that potassium efflux is a trigger for inflammasome activation, the interaction between mycobacterial infection, potassium efflux, and inflammasome activation has not been investigated. Here, we use <i>Mycobacterium marinum</i> infection of zebrafish embryos and <i>Mycobacterium tuberculosis</i> infection of THP-1 cells to demonstrate that pathogenic mycobacteria up-regulate the host WNK signalling pathway kinases SPAK and OXSR1 which control intracellular potassium balance. We show that genetic depletion or inhibition of OXSR1 decreases bacterial burden and intracellular potassium levels. The protective effects of OXSR1 depletion are at least partially mediated by NLRP3 inflammasome activation, caspase-mediated release of IL-1β, and downstream activation of protective TNF-α. The elucidation of this druggable pathway to potentiate inflammasome activation provides a new avenue for the development of host-directed therapies against intracellular infections.Life science allianceOXSR1 inhibits inflammasome activation by limiting potassium efflux during mycobacterial infection.PMC9107790G197581APP1099912, APP1053407APP1153493H18/31086Oehlers SHHortle EPinello NHansbro PMWright KFontaine ARTran VLWong JJO'Rourke MBBritton WJfalseOXSR1 inhibits inflammasome activation by limiting potassium efflux during mycobacterial infection.Pathogenic mycobacteria inhibit inflammasome activation to establish infection. Although it is known that potassium efflux is a trigger for inflammasome activation, the interaction between mycobacterial infection, potassium efflux, and inflammasome activation has not been investigated. Here, we use <i>Mycobacterium marinum</i> infection of zebrafish embryos and <i>Mycobacterium tuberculosis</i> infection of THP-1 cells to demonstrate that pathogenic mycobacteria up-regulate the host WNK signalling pathway kinases SPAK and OXSR1 which control intracellular potassium balance. We show that genetic depletion or inhibition of OXSR1 decreases bacterial burden and intracellular potassium levels. The protective effects of OXSR1 depletion are at least partially mediated by NLRP3 inflammasome activation, caspase-mediated release of IL-1β, and downstream activation of protective TNF-α. The elucidation of this druggable pathway to potentiate inflammasome activation provides a new avenue for the development of host-directed therapies against intracellular infections.2022-01-01T00:00:00Z2022 Sep2026-05-09T18:55:33.31Z2025-05-18T12:05:07.516ZS-EPMC91077903554529510.26508/lsa.202201476