Parkinson's disease kinase LRRK2 coordinates a cell-intrinsic itaconate-dependent defence pathway against intracellular Salmonella.

Autor: Lian H; Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT, USA.; Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, China., Park D; Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT, USA.; Microbial Science Institute, Yale University School of Medicine, New Haven, CT, USA.; Department of Integrative Structural and Computational Biology, Scripps Research, La Jolla, CA, USA., Chen M; Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT, USA.; Institute of Infectious Diseases, Shenzhen Bay Laboratory, Shenzhen, China., Schueder F; Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT, USA.; Department of Cell Biology, Yale University School of Medicine, New Haven, CT, USA., Lara-Tejero M; Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT, USA., Liu J; Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT, USA.; Microbial Science Institute, Yale University School of Medicine, New Haven, CT, USA., Galán JE; Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT, USA. jorge.galan@yale.edu.
Jazyk: angličtina
Zdroj: Nature microbiology [Nat Microbiol] 2023 Oct; Vol. 8 (10), pp. 1880-1895. Date of Electronic Publication: 2023 Aug 28.
DOI: 10.1038/s41564-023-01459-y
Abstrakt: Cell-intrinsic defences constitute the first line of defence against intracellular pathogens. The guanosine triphosphatase RAB32 orchestrates one such defence response against the bacterial pathogen Salmonella, through delivery of antimicrobial itaconate. Here we show that the Parkinson's disease-associated leucine-rich repeat kinase 2 (LRRK2) orchestrates this defence response by scaffolding a complex between RAB32 and aconitate decarboxylase 1, which synthesizes itaconate from mitochondrial precursors. Itaconate delivery to Salmonella-containing vacuoles was impaired and Salmonella replication increased in LRRK2-deficient cells. Loss of LRRK2 also restored virulence of a Salmonella mutant defective in neutralizing this RAB32-dependent host defence pathway in mice. Cryo-electron tomography revealed tether formation between Salmonella-containing vacuoles and host mitochondria upon Salmonella infection, which was significantly impaired in LRRK2-deficient cells. This positions LRRK2 centrally within a host defence mechanism, which may have favoured selection of a common familial Parkinson's disease mutant allele in the human population.
(© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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