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Updated: May 10, 2025

Author Spotlight: A Selective Luciferase-Based Assay for Monitoring ATG4B 27 Activity in Cells
Published on: June 30, 2023
ATP2A2 regulates STING1/MITA-driven signal transduction including selective autophagy
Xue Yang1,2, Linyue Lv1,2, Yuelan Zhang1,2
1Department of Rheumatology and Immunology, State Key Laboratory of Virology and Biosafety, Zhongnan Hospital, Wuhan University, Wuhan, China.
Abstract:
STING1/MITA not only induces innate immune responses but also triggers macroautophagy/autophagy to selectively degrade signaling molecules. However, the molecular mechanisms regulating STING1-mediated selective autophagy remain unclear. Here, we first report that ATP2A2 directly interacts with STING1, regulating STING1-mediated innate immune response by modulating its polymerization and trafficking, thereby inhibiting DNA virus infection. Notably, while screening for reticulophagy receptors involved in STING1-mediated selective autophagy, we identified SEC62 as an important receptor protein in STING1-mediated reticulophagy. Mechanistically, SEC62 strengthens its interaction with STING1 upon activation and concurrently facilitates STING1-mediated reticulophagy upon starvation, which are dependent on ATP2A2. Furthermore, knocking down SEC62 in WT cells inhibits STING1-mediated MAP1LC3B/LC3B lipidation and autophagosome formation, an effect that is lost in ATP2A2 knockout cells, suggesting that SEC62's role in STING1-mediated selective autophagy is ATP2A2 dependent. Thus, our findings identify the reticulophagy receptor SEC62 as a novel receptor protein regulating STING1-mediated selective autophagy, providing new insight into the mechanism regarding a reticulophagy receptor in the process of STING1-induced selective autophagy.Abbrevations: aa: amino acids; AP-MS: affinity tag purification-mass spectrometry; ATP2A1: ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 1; ATP2A2: ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 2; ATP2A3: ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 3; CANX: calnexin; CCPG1: cell cycle progression 1; CGAS: cyclic GMP-AMP synthase; ctDNA: calf thymus DNA; dsRNA: double-stranded RNA; diABZI: diamidobenzimidazole; ER: endoplasmic reticulum; ERGIC: ER-Golgi intermediate compartment; EBSS: Earle's Balanced Salt Solution; EV: empty vector; FL: full length; GOLGA2/GM130: golgin A2; HSV-1: herpes simplex virus type 1; IRF3: interferon regulatory factor 3; IFNs: type I interferons; ISD: interferon stimulatory DNA; KO: knockout; MAVS: mitochondrial antiviral signaling protein; MOI: multiplicity of infection; poly(I:C): polyinosinic-polycytidylic acid; NBR1: NBR1 autophagy cargo receptor; PRR: pattern recognition receptor; reticulophagy: selective autophagic degradation of the ER; RETREG1/FAM134B: reticulophagy regulator 1; RIGI: RNA sensor RIG-I; RTN3L: reticulon 3; SEC62: SEC62 homolog, preprotein translocation factor; SeV: Sendai virus; STIM1: stromal interaction molecule 1; STING1/MITA: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1; TEX264: testis expressed 264, ER-phagy receptor; TMX1: thioredoxin related transmembrane protein 1; VSV: vesicular stomatitis virus; VACV: vaccinia virus; ZMPSTE24: zinc metallopeptidase STE24.
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