# Mycobacterium tuberculosis modulates phosphorylation of host ATP6V1E1 to promote intracellular survival

## TL;DR

Mycobacterium tuberculosis prevents lysosomal acidification by phosphorylating a host protein, helping it survive inside cells.

## Contribution

The study identifies a novel mechanism by which Mtb modulates host V-ATPase through phosphorylation of ATP6V1E1.

## Key findings

- Mtb secretes Rv1184/Chp2, which promotes phosphorylation of ATP6V1E1 at Tyr56/57.
- Phosphorylation of ATP6V1E1 inhibits V-ATPase assembly and lysosomal acidification.
- BMX tyrosine kinase is involved in ATP6V1E1 phosphorylation, and its inhibition reduces Mtb growth.

## Abstract

Intracellular pathogens such as Mycobacterium tuberculosis (Mtb) can promote their survival within infected cells by preventing lysosomal acidification. Here, we report that Mtb secretes a protein (Rv1184, or acyltransferase Chp2) that inhibits lysosomal acidification by targeting the host vacuolar ATPase (V-ATPase). We show that phosphorylation of the V-ATPase E1 subunit (ATP6V1E1) at Tyr56/57 suppresses lysosomal acidification through inhibition of V-ATPase assembly. Further investigation reveals that tyrosine kinase BMX promotes phosphorylation of ATP6V1E1. Strikingly, Chp2 increases BMX-dependent phosphorylation of ATP6V1E1, apparently by directly binding ATP6V1E1 and facilitating its interaction with BMX. Furthermore, inhibition of BMX impairs Mtb growth within macrophages and in mice. Thus, our work reveals a mechanism for the regulation of lysosomal acidification and suggests lysosomal acidification modulation as a potential approach for host-directed therapy against Mtb.

Intracellular pathogens such as Mycobacterium tuberculosis can promote their survival within infected cells by preventing lysosomal acidification. Here, the authors show that M. tuberculosis secretes a protein that promotes phosphorylation of a subunit of the host vacuolar ATPase, thus inhibiting V-ATPase assembly and lysosomal acidification.