2. Academic Validation
  3. ATG16L1 controls mammalian vacuolar proton ATPase

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

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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