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<p>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.</p>

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Rab14 restricts pathogens by promoting V-ATPase lysosomal delivery to drive lysosomal acidification

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月2日

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  • 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

摘要

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.