ESX-1 substrates ESAT-6 and CFP-10 limit cGAS-STING activation via DNA and Zn2+ restriction

ESX-1 substrates ESAT-6 and CFP-10 constrain cGAS-STING signaling during Mycobacterium marinum infection by limiting DNA ligand availability and Zn2+-dependent activation conditions.

• Why it matters: Although ESX-1 exposes mycobacterial DNA to cytosolic cGAS-STING, the response is not overwhelming, implying additional biochemical control layers.
• What they did: Purified Mycobacterium tuberculosis CFP-10 is a metal-dependent 5'-3' exonuclease-like enzyme that preferentially degrades linear DNA, while purified ESAT-6 binds Zn2+ to limit Zn2+-dependent cGAS activation; during M. marinum infection, substrate loss augmented interferon-associated responses.
• The result: Wild-type alleles restored immune suppression, but DNA-processing-defective CFP-10 or Zn2+-binding-defective ESAT-6 variants did not; these genotype effects were largely abolished in cGas-/- and Sting-/- macrophages, and the double mutant was attenuated in zebrafish and mice with diminished enhanced immune activation in cGas-/- mice.