ATP2A2 regulates STING1/MITA-driven signal transduction including selective autophagy

Area of Science:

• Immunology
• Cell Biology
• Molecular Biology

Background:

• STING1 (stimulator of interferon response cGAMP interactor 1) induces innate immunity and autophagy for signaling molecule degradation.
• The precise molecular mechanisms governing STING1-mediated selective autophagy remain incompletely understood.

Purpose of the Study:

• To elucidate the molecular mechanisms regulating STING1-mediated selective autophagy.
• To identify novel receptor proteins involved in STING1-mediated reticulophagy.

Main Methods:

• Investigated the interaction between ATP2A2 (ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 2) and STING1.
• Screened for reticulophagy receptors involved in STING1-mediated selective autophagy, identifying SEC62 (SEC62 homolog, preprotein translocation factor).
• Utilized knockdown and knockout cell models (WT and ATP2A2 KO) to assess the role of SEC62 in STING1-mediated autophagy (MAP1LC3B/LC3B lipidation and autophagosome formation).

Main Results:

• ATP2A2 directly interacts with STING1, modulating its polymerization and trafficking to inhibit DNA virus infection.
• SEC62 functions as a reticulophagy receptor in STING1-mediated selective autophagy, with its interaction with STING1 and facilitation of reticulophagy dependent on ATP2A2.
• Knockdown of SEC62 impairs STING1-mediated autophagy in WT cells, but this effect is abolished in ATP2A2 knockout cells, confirming ATP2A2 dependence.

Conclusions:

• SEC62 is identified as a novel receptor protein regulating STING1-mediated selective autophagy.
• The findings reveal a new mechanism involving SEC62 in STING1-induced selective autophagy, highlighting the crucial role of ATP2A2.