The V-ATPase/ATG16L1 axis is controlled by the V1H subunit
Neurons
Mice, Knockout
Vacuolar Proton-Translocating ATPases
FOS: Clinical medicine
Induced Pluripotent Stem Cells
Immunology
Autophagy-Related Proteins
Infectious Disease
Autophagy-Related Protein 8 Family
Cell Biology
Biochemistry & Proteomics
Mice, Inbred C57BL
Mice
HEK293 Cells
Influenza, Human
Autophagy
Humans
Animals
Carrier Proteins
Protein Binding
Signal Transduction
DOI:
10.1016/j.molcel.2024.07.003
Publication Date:
2024-07-31T14:39:02Z
AUTHORS (15)
ABSTRACT
Defects in organellar acidification indicate compromised or infected compartments. Recruitment of the autophagy-related ATG16L1 complex to pathologically neutralized organelles targets ubiquitin-like ATG8 molecules to perturbed membranes. How this process is coupled to proton gradient disruption is unclear. Here, we reveal that the V1H subunit of the vacuolar ATPase (V-ATPase) proton pump binds directly to ATG16L1. The V1H/ATG16L1 interaction only occurs within fully assembled V-ATPases, allowing ATG16L1 recruitment to be coupled to increased V-ATPase assembly following organelle neutralization. Cells lacking V1H fail to target ATG8s during influenza infection or after activation of the immune receptor stimulator of interferon genes (STING). We identify a loop within V1H that mediates ATG16L1 binding. A neuronal V1H isoform lacks this loop and is associated with attenuated ATG8 targeting in response to ionophores in primary murine and human iPSC-derived neurons. Thus, V1H controls ATG16L1 recruitment following proton gradient dissipation, suggesting that the V-ATPase acts as a cell-intrinsic damage sensor.
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CITATIONS (16)
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