Itaconate transport across the plasma membrane and Salmonella-containing vacuole via MCT1/4 modulates macrophage antibacterial activity

Qingcai Meng, Chengxi Li, Yuping Cai, Ying Chen, Xiaoqing Chen, Xin Wang, Biling Zhang, Yue Zhang, Feng Liu and Meixin Chen ()
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Qingcai Meng: Shenzhen Bay Laboratory, Institute of Infectious Diseases
Chengxi Li: Shenzhen Bay Laboratory, Institute of Infectious Diseases
Yuping Cai: Chinese Academy of Sciences, Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry
Ying Chen: Shenzhen Bay Laboratory, Institute of Infectious Diseases
Xiaoqing Chen: Shenzhen Bay Laboratory, Institute of Infectious Diseases
Xin Wang: Shenzhen Bay Laboratory, Institute of Infectious Diseases
Biling Zhang: Shenzhen Bay Laboratory, Institute of Infectious Diseases
Yue Zhang: Shenzhen Bay Laboratory, Institute of Infectious Diseases
Feng Liu: Shenzhen Bay Laboratory, Institute of Infectious Diseases
Meixin Chen: Shenzhen Bay Laboratory, Institute of Infectious Diseases

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Itaconate accumulates in macrophages upon bacterial infection, and manifests antibacterial activity. Convincing evidence substantiates that itaconate is transported across the plasma membrane and vacuolar membrane, but the molecular bases underlying bidirectional transport of itaconate across membranes and its effects on intracellular bacterial replication are less known. Here, we identify MCT1 and MCT4 as bidirectional transporters of itaconate. In addition to modulating itaconate concentration as transporters at the plasma membrane, MCT1 and MCT4 function as itaconate transporters at Salmonella-containing vacuole (SCV). Upon Salmonella infection, MCT1 and MCT4 transport itaconate into SCV facilitated by RAB32. Itaconate is also secreted out of cells through MCT1 and MCT4 as the infection persists. The suppression of MCT1 and MCT4-dependent itaconate secretion increases the overall concentration of itaconate and the proportion of itaconate-targeted Salmonella intracellularly, consequently inhibiting Salmonella replication. Our study thus offers valuable insights into itaconate transport during bacterial infection and provides proof of principle for the development of itaconate-dependent therapeutic strategies.

Date: 2025
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DOI: 10.1038/s41467-025-65582-6

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