ATG16L1 controls mammalian vacuolar proton ATPase

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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Publication Details

Journal
The Journal of Cell Biology
Published
2025-09-09
DOI
https://doi.org/10.1083/jcb.202503166
Citations
2
Primary Topic
ATP Synthase and ATPases Research
Type
article
Field-Weighted Citation Impact
1.61
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article

ATG16L1 controls mammalian vacuolar proton ATPase

Ruheena Javed, Thomas Wileman, Masroor Ahmad Paddar, Soumya Ranjan Mishra et al.
2 citations
The Journal of Cell Biology
ATP Synthase and ATPases Research
1.61
article

ATG16L1 controls mammalian vacuolar proton ATPase

Ruheena Javed, Thomas Wileman, Masroor Ahmad Paddar, Soumya Ranjan Mishra, Einar S Trosdal, Michelle Salemi, Lee Allers, Shawn B. Bratton, Prithvi Reddy Akepati, Thabata Duque, Brett S. Phinney, Vojo Deretić, Michal Mudd
article en
2 citations

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.

The Journal of Cell BiologyVol. 224(10)
University of East Anglia (GB), The University of Texas MD Anderson Cancer Center (US), University of New Mexico (US), University of California, Davis (US)
Openalex Percentile: Top 15%
ATP Synthase and ATPases Research
1.61
DOIOpen Access PDFOpenAlex
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ATG16L1 controls mammalian vacuolar proton ATPase — Ruheena Javed, Thomas Wileman, et al. · The Journal of Cell Biology (2025) | TGRS Research Map | TGRS