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

Area of Science:

• Immunology
• Cell Biology
• Microbiology

Background:

• Host restriction factors are crucial for intrinsic immunity against pathogens.
• While viral restriction factors are well-studied, bacterial counterparts with broad-spectrum activity are underexplored.
• Lysosomal acidification is a key cellular process for pathogen clearance.

Purpose of the Study:

• To identify novel host restriction factors with broad-spectrum antimicrobial activity.
• To elucidate the mechanism by which these factors restrict pathogen growth.
• To explore potential targets for host-directed therapy (HDT) against infectious diseases.

Main Methods:

• Screening for host factors that promote lysosomal acidification.
• Identifying Rab14 through functional screening.
• Investigating the molecular interactions of Rab14 with CAMK2D and V-ATPase components.
• Assessing the impact of Rab14 on pathogen clearance in cellular models.

Main Results:

• Rab14 was identified as a host restriction factor with broad-spectrum activity against bacteria and viruses.
• Rab14 enhances lysosomal acidification by regulating V-ATPase trafficking.
• Mechanistically, Rab14 binds CAMK2D, suppressing V0a1 phosphorylation and promoting V-ATPase delivery to lysosomes.
• This Rab14-CAMK2D-V-ATPase axis facilitates pathogen clearance.

Conclusions:

• Rab14 represents a novel intrinsic immune mechanism against diverse pathogens.
• The Rab14-CAMK2D-V-ATPase pathway is a potential therapeutic target for infectious diseases.
• This finding expands the understanding of host-directed therapies against drug-resistant pathogens.