T6SS translocates a micropeptide to suppress STING-mediated innate immunity by sequestering manganese

Although emerging evidence suggests that the STING-mediated immune response pathway plays a crucial role in microbial pathogen infection, few bacterial effectors have been reported to target this pathway. Here, we identified a T6SS-secreted micropeptide, TssS, which is crucial for the pathogenesis of Yptb. Distinct from traditional bacterial effectors that target host proteins or other macromolecules, TssS inhibits STING oligomerization and downstream signaling pathways by chelating Mn2+. Thus, TssS mediates a previously unrecognized immune evasion mechanism by modulating the availability of immunostimulatory Mn2+ in host cells. This finding reveals a strategy to modulate the STING pathway by microbial pathogens, provides a new perspective on the role of T6SS in pathogenesis, and highlights the importance of micropeptides in pathogen–host interactions.