RAB22A介导的非经典自噬引发的激活STING的细胞间转移促进了抗肿瘤免疫。
Intercellular transfer of activated STING triggered by RAB22A-mediated non-canonical autophagy promotes antitumor immunity.
发表日期：2022 Dec
作者：
Ying Gao, Xueping Zheng, Boyang Chang, Yujie Lin, Xiaodan Huang, Wen Wang, Shirong Ding, Weixiang Zhan, Shang Wang, Beibei Xiao, Lanqing Huo, Youhui Yu, Yilin Chen, Run Gong, Yuanzhong Wu, Ruhua Zhang, Li Zhong, Xin Wang, Qiuyan Chen, Song Gao, Zhengfan Jiang, Denghui Wei, Tiebang Kang
来源：
CELL RESEARCH
摘要：
STING是一种存在于内质网（ER）跨膜蛋白，可以在接受cGAMP刺激后介导先天性免疫激活，并通过自噬进行降解。本研究报道，激活的STING可以在细胞间转移，以促进抗肿瘤免疫，这一过程由RAB22A介导的非经典自噬触发。机制上，RAB22A参与PI4K2A的生成，生成PI4P进而招募Atg12-Atg5-Atg16L1复合物，诱导ER来源于RAB22A介导的非经典自噬体的形成，其中胜肽激动剂或化疗放疗激活的STING被包装。这种由RAB22A诱导的自噬体会与RAB22A正的早期内质体融合，形成一个新的细胞器，我们称之为Rafsosome（与早期内质体融合的RAB22A介导的非经典自噬体）。同时，RAB22A失活RAB7抑制Rafsosome与溶酶体的融合，从而促进带有活化STING的内泡的自噬体的分泌，形成一种新的外泌体，我们称之为R-EV（RAB22A诱导的外泌体）。激活STING的R-EV诱导受体细胞在肿瘤微环境中释放IFNβ，从而促进抗肿瘤免疫。一致性的是，RAB22A增强了小鼠中STING激动剂diABZI的抗肿瘤效应，高水平的RAB22A预示着鼻咽癌患者化疗放疗后的良好生存率。我们的发现揭示了Rafsosome调节激活STING的细胞间转移，以触发和传播抗肿瘤免疫，而非经典自噬体里的内部小泡由ER来源的，并以R-EV分泌出去，为理解细胞间膜蛋白的交流提供了新的视角。©2022作者。
STING, an endoplasmic reticulum (ER) transmembrane protein, mediates innate immune activation upon cGAMP stimulation and is degraded through autophagy. Here, we report that activated STING could be transferred between cells to promote antitumor immunity, a process triggered by RAB22A-mediated non-canonical autophagy. Mechanistically, RAB22A engages PI4K2A to generate PI4P that recruits the Atg12-Atg5-Atg16L1 complex, inducing the formation of ER-derived RAB22A-mediated non-canonical autophagosome, in which STING activated by agonists or chemoradiotherapy is packaged. This RAB22A-induced autophagosome fuses with RAB22A-positive early endosome, generating a new organelle that we name Rafeesome (RAB22A-mediated non-canonical autophagosome fused with early endosome). Meanwhile, RAB22A inactivates RAB7 to suppress the fusion of Rafeesome with lysosome, thereby enabling the secretion of the inner vesicle of the autophagosome bearing activated STING as a new type of extracellular vesicle that we define as R-EV (RAB22A-induced extracellular vesicle). Activated STING-containing R-EVs induce IFNβ release from recipient cells to the tumor microenvironment, promoting antitumor immunity. Consistently, RAB22A enhances the antitumor effect of the STING agonist diABZI in mice, and a high RAB22A level predicts good survival in nasopharyngeal cancer patients treated with chemoradiotherapy. Our findings reveal that Rafeesome regulates the intercellular transfer of activated STING to trigger and spread antitumor immunity, and that the inner vesicle of non-canonical autophagosome originated from ER is secreted as R-EV, providing a new perspective for understanding the intercellular communication of organelle membrane proteins.© 2022. The Author(s).