OXSR1 inhibits inflammasome activation by limiting potassium efflux during mycobacterial infection.

Hortle, E; Tran, VL; Wright, K; Fontaine, AR; Pinello, N; O'Rourke, MB; Wong, JJ-L; Hansbro, PM; Britton, WJ; Oehlers, SH

OXSR1 inhibits inflammasome activation by limiting potassium efflux during mycobacterial infection.

Hortle, E

Tran, VL Wright, K Fontaine, AR Pinello, N O'Rourke, MB Wong, JJ-L Hansbro, PM Britton, WJ Oehlers, SH

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Publisher:: LIFE SCIENCE ALLIANCE LLC
Publication Type:: Journal Article
Citation:: Life Sci Alliance, 2022, 5, (9), pp. e202201476
Issue Date:: 2022-09

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Field	Value	Language
dc.contributor.author	Hortle, E https://orcid.org/0000-0001-9633-5638
dc.contributor.author	Tran, VL
dc.contributor.author	Wright, K
dc.contributor.author	Fontaine, AR
dc.contributor.author	Pinello, N
dc.contributor.author	O'Rourke, MB
dc.contributor.author	Wong, JJ-L
dc.contributor.author	Hansbro, PM
dc.contributor.author	Britton, WJ
dc.contributor.author	Oehlers, SH
dc.date.accessioned	2022-07-05T05:37:38Z
dc.date.available	2022-04-19
dc.date.available	2022-07-05T05:37:38Z
dc.date.issued	2022-09
dc.identifier.citation	Life Sci Alliance, 2022, 5, (9), pp. e202201476
dc.identifier.issn	2575-1077
dc.identifier.issn	2575-1077
dc.identifier.uri	http://hdl.handle.net/10453/158662
dc.description.abstract	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 Mycobacterium marinum infection of zebrafish embryos and Mycobacterium tuberculosis 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.
dc.format	Electronic-Print
dc.language	eng
dc.publisher	LIFE SCIENCE ALLIANCE LLC
dc.relation	http://purl.org/au-research/grants/nhmrc/1153493
dc.relation.ispartof	Life Sci Alliance
dc.relation.isbasedon	10.26508/lsa.202201476
dc.rights	License: This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/ licenses/by/4.0/)
dc.rights	info:eu-repo/semantics/restrictedAccess
dc.subject.mesh	Animals
dc.subject.mesh	Inflammasomes
dc.subject.mesh	Mycobacterium
dc.subject.mesh	NLR Family, Pyrin Domain-Containing 3 Protein
dc.subject.mesh	Potassium
dc.subject.mesh	Signal Transduction
dc.subject.mesh	Zebrafish
dc.subject.mesh	Animals
dc.subject.mesh	Zebrafish
dc.subject.mesh	Mycobacterium
dc.subject.mesh	Potassium
dc.subject.mesh	Signal Transduction
dc.subject.mesh	Inflammasomes
dc.subject.mesh	NLR Family, Pyrin Domain-Containing 3 Protein
dc.title	OXSR1 inhibits inflammasome activation by limiting potassium efflux during mycobacterial infection.
dc.type	Journal Article
utslib.citation.volume	5
utslib.location.activity	United States
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
utslib.copyright.status	recently_added	*
dc.date.updated	2022-07-05T05:37:34Z
pubs.issue	9
pubs.publication-status	Published online
pubs.volume	5
utslib.citation.issue	9

Abstract:

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 Mycobacterium marinum infection of zebrafish embryos and Mycobacterium tuberculosis 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.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/158662