Extended-synaptotagmin 1 engages in unconventional protein secretion mediated via SEC22B<sup>+</sup>vesicle pathway in liver cancer-Reference-Cited by-同舟云学术

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

Published:2022-08-31 Issue:36 Volume:119 Page:
ISSN:0027-8424
Container-title:Proceedings of the National Academy of Sciences
language:en
Short-container-title:Proc. Natl. Acad. Sci. U.S.A.

Author:

Yamada Kohji¹^ORCID,Motohashi Saya¹^ORCID,Oikawa Tsunekazu²,Tago Naoko¹^ORCID,Koizumi Rei¹^ORCID,Ono Masaya³,Tachibana Toshiaki⁴,Yoshida Ayano¹,Yoshida Saishu¹^ORCID,Shimoda Masayuki⁵,Oka Masahiro⁶,Yoneda Yoshihiro⁷,Yoshida Kiyotsugu¹^ORCID

Affiliation:

1. Department of Biochemistry, Jikei University School of Medicine, Tokyo 105-8461, Japan

2. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Jikei University School of Medicine, Tokyo 105-8461, Japan

3. Department of Clinical Proteomics, National Cancer Center Research Institute, Tokyo 104-0045, Japan

4. Core Research Facilities for Basic Science, Research Center for Medical Sciences, Jikei University School of Medicine, Tokyo 105-8461, Japan

5. Department of Pathology, Jikei University School of Medicine, Tokyo 105-8461, Japan

6. Laboratory of Nuclear Transport Dynamics, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka 567-0085, Japan

7. National Institutes of Biomedical Innovation, Health and Nutrition, Osaka 567-0085, Japan

Abstract

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.

Funder

Japan Agency for Medical Research and Development

MEXT | Japan Society for the Promotion of Science

Takeda Science Foundation

Science Research Promotion Fund

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

Link

https://pnas.org/doi/pdf/10.1073/pnas.2202730119

Reference44 articles.