An unconventional autophagic pathway that inhibits ATP secretion during apoptotic cell death

Area of Science:

• Cellular Biology
• Immunology
• Autophagy Research

Background:

• Damage-Associated Molecular Patterns (DAMPs) dictate apoptosis immunogenicity, but their exposure mechanisms remain elusive.
• Adenosine triphosphate (ATP) is a key DAMP released during immunogenic apoptosis.
• Understanding DAMP release control is crucial for modulating immune responses to cell death.

Purpose of the Study:

• To elucidate the mechanisms controlling DAMP exposure during apoptosis.
• To identify pathways that regulate ATP release from dying cells.
• To investigate the role of unconventional autophagy in apoptotic cell death.

Main Methods:

• Investigated the interaction of mitochondrial BAK with prohibitin and stomatin-1 in dying cells.
• Characterized the formation of a BAK-specific interactome involving ATG16L1.
• Analyzed the role of this complex in inducing unconventional autophagy and ATP sequestration.
• Assessed the impact of pathway interference on ATP release and phagocyte activation.

Main Results:

• An unconventional autophagic pathway was identified that sequesters intracellular ATP.
• Mitochondrial BAK interacts with prohibitin and stomatin-1, engaging ATG16L1 to form LC3-positive vesicles containing ATP.
• Interfering with this pathway increased extracellular ATP release and enhanced phagocyte activation.

Conclusions:

• A novel unconventional autophagic pathway actively sequesters ATP within dying cells.
• This ATP sequestration mechanism promotes the immunosilent nature of apoptotic cell death.
• The findings reveal a critical regulator of DAMP release and immune tolerance during apoptosis.