Nat Commun. 2026 Mar 02.
Zehui Lei,
Lihua Qiang,
Pupu Ge,
Yuyun Qiang,
Tergel Sun,
Qiyao Chai,
Yiru Wang,
Shan Lv,
Changgen Qiu,
Zhe Lu,
Mengyuan Zhao,
Zhuo Zhao,
You Wu,
Xinwen Zhang,
Yanzhao Zhong,
Bingxi Li,
Lingqiang Zhang,
Jing Wang,
Cui Hua Liu.
Host restriction factors mediate intrinsic immunity against infections, thus serving as promising targets for host-directed therapy (HDT) against drug-resistant pathogens. While restriction factors counteracting viruses have been extensively studied, those targeting bacteria, particularly those with broad-spectrum activity, remain largely unexplored. Here, through screening for host factors promoting lysosomal acidification, a crucial process clearing pathogens, we identify the host small GTPase Rab14 as a restriction factor with broad-spectrum activity against multiple bacteria and viruses. Mechanistically, upon pathogen infections, GTP-bound Rab14 increases and binds to the calcium/calmodulin-dependent protein kinase type 2 delta (CAMK2D), suppressing CAMK2D-mediated phosphorylation of V0a1, the critical subunit determining V-ATPase localization, thus promoting V0a1 binding to the COPⅡ complex to facilitate V-ATPase trafficking from the endoplasmic reticulum to lysosomes, resulting in lysosomal acidification and pathogen clearance. Taken together, our data demonstrate an unrecognized intrinsic immune mechanism mediated by Rab14-CAMK2D-V-ATPase axis, which might be a promising target for infectious diseases.