ATG16L1 controls mammalian vacuolar proton ATPase

Area of Science:

• Cell Biology
• Molecular Biology
• Immunology

Background:

• Vesicular proton pump V-ATPase is crucial for mammalian cell function and has medical relevance.
• V-ATPase assembly and disassembly, involving cytoplasmic V1 and membrane-embedded V0 domains, dictate its localization and activity.
• ATG16L1 is known for its roles in autophagy and membrane atg8ylation.

Purpose of the Study:

• To investigate the role of mammalian protein ATG16L1 in regulating V-ATPase function.
• To understand how ATG16L1 influences endolysosomal acidification and cellular defense mechanisms.

Main Methods:

• Utilized ATG16L1 knockout models to assess V-ATPase activity and localization.
• Examined the binding affinity of ATG16L1 to V-ATPase.
• Assessed the impact on endolysosomal acidification and control of Mycobacterium tuberculosis infection in mice.

Main Results:

• ATG16L1 knockout led to elevated V-ATPase activity and increased V1 domain presence on endomembranes.
• A higher number of acidified intracellular compartments were observed in ATG16L1 knockout cells.
• ATG16L1's binding to V-ATPase was essential for its inhibitory effect on endolysosomal acidification and for controlling M. tuberculosis infection.

Conclusions:

• ATG16L1 plays a previously unrecognized role in regulating V-ATPase activity and function.
• This regulation is critical for maintaining endolysosomal acidification and host defense against pathogens like Mycobacterium tuberculosis.