鸟苷三磷酸酶家族蛋白Rab32介导的抗菌机制研究

Rab32是鸟苷三磷酸酶家族成员之一，能够通过调节胞内膜泡的运输来协调各种小分子的转运。已有研究表明，Rab32介导的宿主抗Salmonella感染过程具有重要作用，但其中的抗菌效应物仍有待深入挖掘。本研究已表明，定位于线粒体的顺式亚甲基丁二酸脱羧酶（IRG1）可在Salmonella的感染条件下与Rab32发生相互作用，并且IRG1所催化产生的抗菌活性小分子亚甲基丁二酸（Itaconate）可被转运至含Salmonella的囊泡（SCV）中。基于此，我们推测，细胞被Salmonella感染后会迅速上调IRG1的表达并定位至线粒体，同时Rab32迁移至线粒体与IRG1发生相互作用，促进线粒体来源的囊泡（MDVs）的形成，最终生成的大量Itaconate并运输至SCV发挥抗菌作用。本研究进一步加深了人们对宿主体内天然抗菌机制认识，同时也为开发新的抗菌药物及其手段提供了新的理论依据和新的靶点。

Rab32, a member of Rab GTPase family, mediates the transport of various small molecules in cells by regulating the transport of intracellular membrane vesicles. Previous studies have shown Rab32 mediated transport pathway plays an important role in host defense pathway against intracellular bacteria such as Salmonella. However, the antimicrobial factor(s) delivered by Rab32 mediated transport pathway remains to be further explored. Here, we found that cis-methylene succinate decarboxylase (IRG1) localized on mitochondria could interact with Rab32 under Salmonella infection conditions and synthesize itaconate, a metabolite with antimicrobial activity, which could be delivered to Salmonella-containing vesicles (SCV). Based on this, we hypothesize that IRG1 expression could be rapidly upregulated in cells infected with Salmonella, and IRG1 is located on the mitochondria; at the same time, Rab32 could migrate to mitochondria and interact with IRG1 to promote the formation of mitochondrial-derived vesicles (MDVs), which deliver itaconate to Salmonella-containing vesicles (SCV) for antimicrobial function. This study provides a deep understanding of the natural antibacterial mechanisms in the host and promotes the development of new antibacterial drugs.