ATG16L1 controls mammalian vacuolar proton ATPase

  • J Cell Biol. 2025 Oct 6;224(10):e202503166. doi: 10.1083/jcb.202503166.
Thabata L A Duque  1  2 ,  Masroor Paddar  1  2 ,  Einar Trosdal  1  2 ,  Ruheena Javed  1  2 ,  Lee Allers  1  2 ,  Michal H Mudd  1 ,  Prithvi Akepati  3 ,  Soumya R Mishra  1  2 ,  Michelle Salemi  4 ,  Brett Phinney  4 ,  Shawn B Bratton  5 ,  Thomas Wileman  6 ,  Vojo Deretic  1  2
Affiliations
  • 1. Autophagy, Inflammation and Metabolism Center of Biochemical Research Excellence, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
  • 2. Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, NM, USA.
  • 3. Gastroenterology Division, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM, USA.
  • 4. Proteomics Core Facility, UC Davis Genome Center, University of California, Davis, CA, USA.
  • 5. University of Texas MD Anderson Cancer Center , Houston, TX, USA.
  • 6. Norwich Medical School, University of East Anglia , Norwich, UK.
PMID: 40923996 DOI: 10.1083/jcb.202503166
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.

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