Extended-synaptotagmin 1 engages in unconventional protein secretion mediated via SEC22B + vesicle pathway in liver cancer

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 119; no. 36; p. e2202730119
• Main Authors: Yamada, Kohji, Motohashi, Saya, Oikawa, Tsunekazu, Tago, Naoko, Koizumi, Rei, Ono, Masaya, Tachibana, Toshiaki, Yoshida, Ayano, Yoshida, Saishu, Shimoda, Masayuki, Oka, Masahiro, Yoneda, Yoshihiro, Yoshida, Kiyotsugu
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 06-09-2022
• Subjects: Antibodies; Biological Sciences; Cancer; Cell Membrane - metabolism; Endoplasmic reticulum; Endoplasmic Reticulum - metabolism; Hepatocytes; Humans; Kinases; Liver; Liver cancer; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; Microenvironments; Protein kinase C; Protein Transport; Proteins; R-SNARE Proteins - metabolism; Secretion; Synaptotagmin; Synaptotagmin I - metabolism; Tumor Microenvironment; Tumorigenesis; Tumorigenicity; PKCδ; liver cancer; endoplasmic reticulum (ER); SEC22B; cytosolic protein secretion
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2202730119

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.