延伸突触结合蛋白 1 通过 SEC22B 囊泡途径参与肝癌的非常规蛋白分泌。
Extended-synaptotagmin 1 engages in unconventional protein secretion mediated via SEC22B vesicle pathway in liver cancer.
机构信息
Department of Biochemistry, Jikei University School of Medicine, Tokyo 105-8461, Japan.
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 105-8461, Japan.
出版信息
Proc Natl Acad Sci U S A. 2022 Sep 6;119(36):e2202730119. doi: 10.1073/pnas.2202730119. Epub 2022 Aug 31.
Protein secretion in cancer cells defines tumor survival and progression by orchestrating the microenvironment. Studies suggest the occurrence of active secretion of cytosolic proteins in liver cancer and their involvement in tumorigenesis. Here, we investigated the identification of extended-synaptotagmin 1 (E-Syt1), an endoplasmic reticulum (ER)-bound protein, as a key mediator for cytosolic protein secretion at the ER-plasma membrane (PM) contact sites. Cytosolic proteins interacted with E-Syt1 on the ER, and then localized spatially inside SEC22B vesicles of liver cancer cells. Consequently, SEC22B on the vesicle tethered to the PM via Q-SNAREs (SNAP23, SNX3, and SNX4) for their secretion. Furthermore, inhibiting the interaction of protein kinase Cδ (PKCδ), a liver cancer-specific secretory cytosolic protein, with E-Syt1 by a PKCδ antibody, decreased in both PKCδ secretion and tumorigenicity. Results reveal the role of ER-PM contact sites in cytosolic protein secretion and provide a basis for ER-targeting therapy for liver cancer.
蛋白质分泌在癌细胞中通过协调微环境来定义肿瘤的存活和进展。研究表明，肝癌细胞中存在细胞质蛋白的活跃分泌，并且它们参与了肿瘤发生。在这里，我们研究了识别延伸突触结合蛋白 1（E-Syt1），一种内质网（ER）结合蛋白，作为 ER-质膜（PM）接触部位细胞质蛋白分泌的关键介质。细胞质蛋白在内质网上与 E-Syt1 相互作用，然后在肝癌细胞的 SEC22B 囊泡内空间定位。结果，SEC22B 囊泡通过 Q-SNAREs（SNAP23、SNX3 和 SNX4）与 PM 连接，用于其分泌。此外，通过 PKCδ 抗体抑制蛋白激酶 Cδ（PKCδ），一种肝癌特异性分泌细胞质蛋白，与 E-Syt1 的相互作用，既减少了 PKCδ 的分泌，也减少了肿瘤发生。结果揭示了 ER-PM 接触部位在细胞质蛋白分泌中的作用，并为 ER 靶向治疗肝癌提供了基础。
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