The V-ATPase/ATG16L1 axis is controlled by the V₁H subunit.

Area of Science:

• Cell Biology
• Autophagy
• Molecular Mechanisms

Background:

• Organellar acidification defects signal compromised cellular compartments.
• The autophagy-related ATG16L1 complex targets ATG8 proteins to neutralized organelles.
• The link between proton gradient disruption and ATG8 targeting remains unclear.

Purpose of the Study:

• To elucidate the mechanism coupling organellar proton gradient disruption to ATG16L1 complex recruitment.
• To identify the molecular players involved in targeting ATG8 to perturbed membranes.

Main Methods:

• Investigated the interaction between V-ATPase V1H subunit and ATG16L1.
• Utilized influenza infection and STING activation models.
• Examined ATG8 targeting in cells lacking V1H and in primary neurons with a V1H isoform lacking a specific loop.

Main Results:

• The V1H subunit of V-ATPase directly binds ATG16L1.
• This interaction is specific to fully assembled V-ATPases and occurs upon organelle neutralization.
• V1H deficiency impairs ATG8 targeting during influenza infection and STING activation.
• A specific loop in V1H mediates ATG16L1 binding; its absence in a neuronal isoform attenuates ATG8 targeting.

Conclusions:

• V-ATPase V1H subunit is essential for recruiting ATG16L1 to damaged organelles.
• The V-ATPase functions as a cell-intrinsic damage sensor by coupling proton gradient dissipation to the autophagy machinery.
• This mechanism is critical for cellular defense against pathogens and immune signaling.