Autophagy. 2025 Apr 21.
Chen Chen,
Guoxu Liu,
Kehan Xu,
Aibao Chen,
Ziyang Cheng,
Xueping Yan,
Ting Zhang,
Yan Sun,
Tian Yu,
Jiayao Wang,
Shuangshuang Luo,
Weiting Zhou,
Shengqun Deng,
Yan Liu,
Yanan Yang.
Rickettsiae are tick-borne pathogens that infect human hosts through poorly characterized mechanisms. Herein, we report that ATG9 (autophagy related 9) plays a previously unrecognized role in inhibiting Rickettsia binding to the host cell surface. Unexpectedly, this new function of ATG9 is likely independent of macroautophagy/autophagy. Instead, ATG9 acts as a host defending factor by binding to XRCC6/KU70, a receptor of the Rickettsia outer-membrane protein rOmpB. Both ATG9 and rOmpB bind to the DNA-binding domain of XRCC6, suggesting a competitive role for ATG9 occupying the binding site of rOmpB to abrogate Rickettsia binding. Furthermore, we show that rapamycin transcriptionally activates ATG9 and inhibits rOmpB-mediated infection in a mouse model. Collectively, our study reveals a novel innate mechanism regulating Rickettsia infection and suggests that agonists of ATG9 May be useful for developing therapeutic strategies for the intervention of rickettsial diseases.
Keywords: Autophagy-related gene; Rickettsia; host defense; infectious disease; rOmpB; tick-borne pathogen