ATG16L1 Controls Mammalian Vacuolar Proton ATPase

Authors

Thabata L A Duque
Masroor Paddar
Einar Trosdal
Ruheena Javed
Lee Allers
Michal H Mudd
Prithvi Akepati
Soumya R Mishra
Michelle Salemi
Brett Phinney
Shawn B Bratton
Thomas Wileman
Vojo Deretic

Language

English

Publication Date

10-6-2025

Journal

Journal of Cell Biology

DOI

10.1083/jcb.202503166

PMID

40923996

PMCID

PMC12705107

PubMedCentral® Posted Date

12-16-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

The mechanisms governing mammalian proton pump V-ATPase function are of fundamental and medical interest. The assembly and disassembly of cytoplasmic V1 domain with the membrane-embedded V0 domain of V-ATPase is a key aspect of V-ATPase localization and function. Here, we show that the mammalian protein ATG16L1, primarily appreciated for its role in canonical autophagy and in noncanonical membrane atg8ylation processes, controls V-ATPase. ATG16L1 knockout elevated V-ATPase activity, increased V1 presence on endomembranes, and increased the number of acidified intracellular compartments. ATG16L1's ability to efficiently bind V-ATPase was required for its inhibitory role in endolysosomal acidification and for control of Mycobacterium tuberculosis infection in mice. These findings uncover a hitherto unappreciated role of ATG16L1 in regulating V-ATPase, a key pump governing acidification and functionality of the endolysosomal system along with its physiological roles.

Keywords

Vacuolar Proton-Translocating ATPases, Animals, Autophagy-Related Proteins, Lysosomes, Humans, Mice, Mice, Knockout, Autophagy, Endosomes, Mycobacterium tuberculosis, Hydrogen-Ion Concentration, HEK293 Cells

Published Open-Access

yes

Recommended Citation

Duque, Thabata L A; Paddar, Masroor; Trosdal, Einar; et al., "ATG16L1 Controls Mammalian Vacuolar Proton ATPase" (2025). Faculty, Staff and Student Publications. 5367.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5367