T6SS translocates a micropeptide to suppress STING-mediated innate immunity by sequestering manganese
Lingfang Zhu, Lei Xu, Chenguang Wang, Changfu Li, Mengyuan Li, Qinmeng Liu, Xiao Wang, Wenhui Yang, Damin Pan, Lingfei Hu, Yadong Yang, Zhiqiang Lu, Yao Wang, Dongsheng Zhou, Zhengfan Jiang, Xihui Shen
Abstract
Significance 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 Mn 2+ . Thus, TssS mediates a previously unrecognized immune evasion mechanism by modulating the availability of immunostimulatory Mn 2+ 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.