STING recruits WIPI2 for autophagosome formation

Area of Science:

• Cellular Biology
• Immunology
• Molecular Biology

Background:

• Autophagy is crucial for cellular homeostasis and is induced by the cGAS-STING pathway.
• The precise mechanisms of STING-mediated autophagosome formation are not fully understood.

Purpose of the Study:

• To elucidate the molecular mechanisms of STING-induced autophagy.
• To identify key protein interactions regulating autophagosome formation downstream of STING.

Main Methods:

• Co-immunoprecipitation assays to detect protein-protein interactions.
• Confocal microscopy to visualize protein localization and autophagosome formation.
• Biochemical assays to assess binding affinities and competitive binding.

Main Results:

• STING directly interacts with WD repeat domain, phosphoinositide interacting 2 (WIPI2).
• STING recruits WIPI2 to STING-positive vesicles, promoting LC3 lipidation and autophagosome formation.
• STING and phosphatidylinositol-3-phosphate (PtdIns3P) competitively bind WIPI2, mutually inhibiting STING-induced and PtdIns3P-dependent autophagy.
• The STING-WIPI2 interaction is essential for clearing cytoplasmic DNA and dampening cGAS-STING signaling.

Conclusions:

• STING directly induces autophagosome formation by interacting with WIPI2, bypassing canonical autophagy initiation machinery.
• This interaction plays a critical role in innate immune responses by clearing cytosolic DNA and resolving STING pathway activation.