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帕金森病激酶 LRRK2 协调细胞内依赖异柠檬酸的防御途径，抵抗细胞内沙门氏菌。

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

机构信息

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.

出版信息

Nat Microbiol. 2023 Oct;8(10):1880-1895. doi: 10.1038/s41564-023-01459-y. Epub 2023 Aug 28.

DOI:10.1038/s41564-023-01459-y
PMID:37640963
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10962312/
Abstract

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.

摘要

细胞内在防御构成了抵抗细胞内病原体的第一道防线。鸟嘌呤三磷酸酶 RAB32 通过输送抗菌衣康酸来协调针对细菌病原体沙门氏菌的这种防御反应。在这里，我们表明帕金森病相关的亮氨酸丰富重复激酶 2 (LRRK2) 通过支架 RAB32 和延胡索酸脱羧酶 1 之间的复合物来协调这种防御反应，该复合物从线粒体前体合成衣康酸。在 LRRK2 缺陷细胞中，衣康酸向含有沙门氏菌的液泡的输送受损，并且沙门氏菌的复制增加。LRRK2 的缺失也恢复了沙门氏菌突变体在小鼠中的毒力，该突变体在中和这种 RAB32 依赖的宿主防御途径方面存在缺陷。冷冻电子断层扫描显示，在沙门氏菌感染后，含有沙门氏菌的液泡与宿主线粒体之间形成了连接，而在 LRRK2 缺陷细胞中，这种连接明显受损。这使得 LRRK2 在宿主防御机制中处于中心位置，这可能有利于在人类中选择常见的家族性帕金森病突变等位基因。

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