Host Translational Control by Stress Granules Promotes Mycobacterium tuberculosis Pathogenesis

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.

• Publication year

  2025

• Venue

  MedComm

• Publication date

  2025-11-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1002/mco2.70479PMID 41221148PMCID 12598499
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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