Itaconate is an effector of a Rab GTPase cell-autonomous host defense pathway against Salmonella
Journal
Science
Journal Volume
369
Journal Issue
6502
Date Issued
2020-07-24
Author(s)
Chen, Meixin
Sun, Hui
Boot, Maikel
Shao, Lin
Wang, Weiwei
Lam, Tukiet T.
Lara-Tejero, Maria
Rego, E. Hesper
Galán, Jorge E.
Abstract
The guanosine triphosphatase (GTPase) Rab32 coordinates a cell-intrinsic host defense mechanism that restricts the replication of intravacuolar pathogens such as Salmonella. Here, we show that this mechanism requires aconitate decarboxylase 1 (IRG1), which synthesizes itaconate, a metabolite with antimicrobial activity. We find that Rab32 interacts with IRG1 on Salmonella infection and facilitates the delivery of itaconate to the Salmonella-containing vacuole. Mice defective in IRG1 rescued the virulence defect of a S. enterica serovar Typhimurium mutant specifically defective in its ability to counter the Rab32 defense mechanism. These studies provide a link between a metabolite produced in the mitochondria after stimulation of innate immune receptors and a cell-autonomous defense mechanism that restricts the replication of an intracellular bacterial pathogen.
Type
journal article