ATP2A2调节STING1/ mita驱动的信号转导，包括选择性自噬。

Autophagy Pub Date : 2025-05-04 DOI:10.1080/15548627.2025.2496786

Xue Yang, Linyue Lv, Yuelan Zhang, Zhuyou Zhang, Shaowei Zeng, Xinyi Zhang, Qinyang Wang, Martin Dorf, Shitao Li, Bishi Fu

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引用次数: 0

摘要

STING1/MITA不仅可以诱导先天免疫应答，还可以触发巨噬/自噬选择性降解信号分子。然而，调控sting1介导的选择性自噬的分子机制尚不清楚。在这里，我们首次报道了ATP2A2直接与STING1相互作用，通过调节其聚合和运输来调节STING1介导的先天免疫反应，从而抑制DNA病毒感染。值得注意的是，在筛选参与sting 1介导的选择性自噬的网状吞噬受体时，我们发现SEC62是sting 1介导的网状吞噬的一个重要受体蛋白。在机制上，SEC62在激活时加强了与STING1的相互作用，同时促进了饥饿时由STING1介导的网状吞噬，这依赖于ATP2A2。此外，在WT细胞中敲低SEC62可抑制sting1介导的MAP1LC3B/LC3B脂化和自噬体的形成，而这种作用在敲除ATP2A2的细胞中是缺失的，这表明SEC62在sting1介导的选择性自噬中的作用是依赖于ATP2A2的。因此，我们的研究结果确定了网状吞噬受体SEC62是一种新的受体蛋白，可以调节sting 1介导的选择性自噬，为研究网状吞噬受体在sting 1诱导的选择性自噬过程中的作用机制提供了新的视角。缩写：aa：氨基酸；AP-MS：亲和标签纯化-质谱法；ATP2A1：肌浆/内质网Ca2+转运1；ATP2A2: atp酶肌浆/内质网Ca2+转运2；ATP2A3: atp酶肌浆/内质网Ca2+转运3；CANX: calnexin;CCPG1：细胞周期进展1；CGAS：环GMP-AMP合成酶；ctDNA：小牛胸腺DNA；dsRNA：双链RNA；diABZI: diamidobenzimidazole;ER：内质网；ERGIC: er -高尔基中间隔室；厄尔平衡盐溶液；EV：空向量；FL：全长；GOLGA2/GM130: golgin A2；HSV-1: 1型单纯疱疹病毒；IRF3：干扰素调节因子3；ifn: I型干扰素；ISD：干扰素刺激DNA；柯:淘汰赛;MAVS：线粒体抗病毒信号蛋白；MOI:感染多重性;poly(I:C)：多肌苷-多胞酸；NBR1: NBR1自噬货物受体；PRR：模式识别受体；网状吞噬：内质网选择性自噬降解；RETREG1/FAM134B：网状吞噬调节因子1；RIGI: RNA传感器RIG-I；RTN3L：网状3；SEC62: SEC62同源物，蛋白前易位因子；SeV：仙台病毒；STIM1：基质相互作用分子1；STING1/MITA：干扰素反应刺激因子cGAMP相互作用因子1；TBK1: TANK结合激酶1；TEX264：睾丸表达264，er吞噬受体；TMX1：硫氧还蛋白相关跨膜蛋白1；水疱性口炎病毒；牛痘病毒；ZMPSTE24：锌金属肽酶

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

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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Autophagy

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