# Host Translational Control by Stress Granules Promotes Mycobacterium tuberculosis Pathogenesis

## TL;DR

Stress granules help Mycobacterium tuberculosis survive by blocking immune responses and mitochondrial function in infected cells.

## Contribution

This study reveals a novel role of stress granules in promoting Mtb pathogenesis through translational and metabolic suppression.

## Key findings

- Mtb-induced stress granules sequester mTORC1 and Ndufa12, suppressing translation and mitochondrial function.
- Disrupting stress granules restores immune responses and limits Mtb growth in macrophages.
- Stress granules link energy stress to immune suppression, enabling Mtb persistence.

## Abstract

Stress granules (SGs) are cytoplasmic condensates that regulate mRNA translation and signaling in response to stress. Although SGs have been widely studied in antiviral responses, their function in bacterial infections is not well understood. Here, we demonstrate that SGs promote Mycobacterium tuberculosis (Mtb) pathogenesis by suppressing mitochondrial metabolism and innate immunity. Quantitative proteomics revealed that Mtb‐induced SGs sequester mTORC1 and suppress cap‐dependent mRNA translation. This leads to decreased expression of proteins necessary for mitochondrial respiration and immune activation in bone marrow‐derived macrophages (BMDMs). Disrupting SG assembly restored mTORC1 signaling, enhanced oxidative phosphorylation, and increased the production of antimicrobial mediators, such as reactive oxygen species, nitric oxide, and proinflammatory cytokines. This restricted intracellular Mtb growth in vitro and in vivo. Mechanistically, intracellular ATP depletion triggered by Mtb phagocytosis was sufficient to drive SG formation, linking energy stress to translational repression. Furthermore, SGs captured Ndufa12, a complex I subunit, thereby impairing mitochondrial electron transport and ATP production. These findings identify SGs as key regulators that couple translational arrest to metabolic and immune suppression, enabling Mtb persistence. Targeting SG formation or function could be a host‐directed strategy to restore mitochondrial activity and strengthen immune responses against Mtb infection.

During Mycobacterium tuberculosis infection, stress granules (SGs) formed in macrophages sequester key signaling and metabolic regulators such as mTORC1 components (mTOR, Raptor) and mitochondrial complex I subunits (Ndufa12), leading to suppressed cap‐dependent translation, reduced mitochondrial activity, and impaired innate immune responses. In contrast, SG‐deficient macrophages (G3bp1/2 dKD) maintain mTORC1 activity and mitochondrial function, resulting in enhanced immune activation and restricted Mtb survival both in vitro and in vivo. These findings reveal SGs as critical regulators of host cell metabolism and immunity during Mtb infection.