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.

Recently, Prof. LIU Cui Hua’s group and Prof. WANG Jing’s group at the Institute of Microbiology of the Chinese Academy of Sciences (IMCAS), in collaborating with Prof. ZHANG Lingqiang from Beijing Institute of Lifeomics, identified the host small GTPase Rab14 as a restriction factor with broad-spectrum activity against multiple bacteria and viruses by promoting V-ATPase lysosomal delivery to drive lysosomal acidification (Figure 1).

Lysosomes are membrane-bound organelles that serve as the primary degradative hubs in cells, playing a pivotal role in the cell-intrinsic defense against a broad spectrum of pathogens. Through screening for host factors that promote lysosomal acidification, a crucial process determining the lysosomal degradative function, the authors found that Rab14 serves as a unique host restriction factor with dual antiviral and antibacterial functions by promoting lysosomal acidification. Mechanistic studies revealed that pathogen infections induce the upregulation of GTP-bound Rab14, which then enhances the interaction between Rab14 and the calcium/calmodulin-dependent protein kinase type 2 delta (CAMK2D). This interaction inhibits CAMK2D-catalyzed phosphorylation of V0a1, the critical subunit protein determining V-ATPase localization. As a result, V0a1 is efficiently loaded onto the COPⅡ complex to mediate the trafficking of V-ATPase from the ER to the Golgi apparatus and subsequently to lysosomes, ultimately promoting lysosomal acidification and pathogen clearance.

In summary, this study advances the understanding of host intrinsic immunity by unveiling a critical role for the restriction factor Rab14 in facilitating V-ATPase trafficking and lysosomal acidification, thereby highlighting a promising HDT strategy for infectious diseases through specifically targeting the Rab14-CAMK2D-V-ATPase axis.

Figure 1. Rab14 restricts pathogens by promoting V-ATPase lysosomal delivery to drive lysosomal acidification (image by Prof. LIU Cui Hua’s group)

Full text links: Rab14 restricts pathogens by promoting V-ATPase lysosomal delivery to drive lysosomal acidification