Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China.
Department of Interventional Radiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
Cell Res. 2022 Dec;32(12):1086-1104. doi: 10.1038/s41422-022-00731-w. Epub 2022 Oct 24.
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.
STING，一种内质网（ER）跨膜蛋白，在 cGAMP 刺激下介导先天免疫激活，并通过自噬降解。在这里，我们报告激活的 STING 可以在细胞间转移，以促进抗肿瘤免疫，这一过程是由 RAB22A 介导的非典型自噬触发的。在机制上，RAB22A 与 PI4K2A 结合以生成 PI4P，招募 Atg12-Atg5-Atg16L1 复合物，诱导 ER 衍生的 RAB22A 介导的非典型自噬体形成，其中激动剂或放化疗激活的 STING 被包装。这种 RAB22A 诱导的自噬体与 RAB22A 阳性早期内体融合，产生一种新的细胞器，我们称之为 Rafeesome（RAB22A 介导的非典型自噬体与早期内体融合）。同时，RAB22A 使 RAB7 失活，抑制 Rafeesome 与溶酶体融合，从而使携带激活的 STING 的自噬体的内囊泡作为一种新的细胞外囊泡分泌出来，我们将其定义为 R-EV（RAB22A 诱导的细胞外囊泡）。含有激活的 STING 的 R-EV 诱导受体细胞向肿瘤微环境释放 IFNβ，促进抗肿瘤免疫。一致地，RAB22A 增强了 STING 激动剂 diABZI 在小鼠中的抗肿瘤作用，并且高 RAB22A 水平预示着接受放化疗的鼻咽癌患者有良好的生存。我们的研究结果表明，Rafeesome 调节激活的 STING 在细胞间的转移，以触发和传播抗肿瘤免疫，并且源自 ER 的非典型自噬体的内囊泡作为 R-EV 分泌，为理解细胞器膜蛋白的细胞间通讯提供了新的视角。
