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Mycobacterial ESAT-6 triggers cGAS-STING pathway via the GSDMD-NT dependent mitochondria dysfunction
Yang Yang1, Jinxia Xu2, Yanping Hu1
1Key Laboratory of Applied Biotechnology on Animal Science & Veterinary Medicine of Zhejiang Province, Zhejiang Engineering Research Center for Veterinary Diagnostics & Advanced Technology, Zhejiang International Science and Technology Cooperation Base for Veterinary Medicine and Health Management, Belt and Road International Joint Laboratory for One Health and Food Safety, China-Australia Joint Laboratory for Animal Health Big Data Analytics, College of Veterinary Medicine of Zhejiang A&F University, Hangzhou, Zhejiang, China.
Abstract:
Mycobacterium tuberculosis (Mtb) remains a global health threat due to its ability to subvert host immune responses. Emerging evidence suggests that Mtb infection induces the production of type I interferons (IFNs), during which cGAS directly binds to Mtb genomic DNA. Here, we demonstrate that ESAT-6, a secreted virulence factor of Mtb, potently induces type I interferon (IFN) responses through a cGAS/STING-dependent signaling axis. Genetic ablation and pharmacological inhibition of cGAS or STING abolished ESAT-6-induced IFN-β production. Mechanistically, ESAT-6 induces mitochondrial dysfunction, characterized by mitochondrial DNA (mtDNA) release and mitochondrial ROS (mtROS) production. Further investigation revealed that ESAT-6 triggers GSDMD cleavage, followed by the formation of GSDMD-NT. GSDMD-NT then translocates to mitochondria, disrupting their integrity and promoting mtDNA and mtROS release. GSDMD deficiency prevented ΔΨm loss, mtDNA/mtROS release, and IFN-β responses. Therefore, our findings establish a novel ESAT-6-GSDMD-mtDNA axis that drives type I IFN responses, providing critical insights into Mtb immune evasion strategies.
Insights
Mycobacterium tuberculosis virulence factor ESAT-6 triggers mitochondrial damage and DNA release, activating type I interferon responses via the GSDMD pathway. This reveals a new mechanism in tuberculosis immune evasion.
Area of Science:
- Immunology
- Microbiology
- Cell Biology
Background:
- Mycobacterium tuberculosis (Mtb) evades host immunity.
- Mtb infection can induce type I interferon (IFN) production.
- The cGAS enzyme binds Mtb DNA during infection.
Purpose of the Study:
- Investigate the role of ESAT-6 in Mtb-induced type I IFN responses.
- Elucidate the signaling pathway involved in ESAT-6 mediated immune activation.
- Understand Mtb immune evasion strategies.
Main Methods:
- Utilized genetic ablation and pharmacological inhibition of cGAS and STING.
- Assessed mitochondrial dysfunction markers like mtDNA and mtROS release.
- Examined the role of Gasdermin D (GSDMD) in the pathway.
Main Results:
- ESAT-6 potently induces type I IFN responses via the cGAS/STING axis.
- ESAT-6 causes mitochondrial dysfunction, releasing mtDNA and mtROS.
- ESAT-6 triggers GSDMD cleavage, leading to mitochondrial damage and IFN-β production.
Conclusions:
- A novel ESAT-6-GSDMD-mtDNA axis drives type I IFN responses in Mtb infection.
- This pathway is crucial for Mtb's ability to subvert host immunity.
- Targeting this axis could offer new therapeutic strategies against tuberculosis.
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