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

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.

Identification of subtype recognition and prognosis model characterized by Antibody-dependent cell phagocytosis related genes in breast cancer

“…Therefore, SEC22B on the vesicles is secreted on the PM by Q-SNAREs (SNAP23, SNX3 and SNX4) (44) . In addition, inhibition of the interaction between protein kinase Cδ (PKCδ) and SYT1 by PKCδ antibody can reduce the secretion and tumorigenicity of PKCδ.…”

“…In addition, inhibition of the interaction between protein kinase Cδ (PKCδ) and SYT1 by PKCδ antibody can reduce the secretion and tumorigenicity of PKCδ. PKCδ is a cytoplasmic protein speci cally secreted by hepatocellular carcinoma (44) . The results revealed the signi cance of ER-PM contact sites in facilitating the secretion of cytoplasmic protein, establishing a foundation for targeted therapies of liver cancer (45) .…”

Extended-Synaptotagmin 1 Enhances Liver Cancer Progression Mediated by the Unconventional Secretion of Cytosolic Proteins

“…Clinical studies have shown that serum PKCδ levels are significantly higher in patients with hepatocellular carcinoma (HCC) than in normal individuals or those with chronic liver disease (chronic hepatitis and cirrhosis) [ 8 ]. Many unconventional secretions, including PKCδ and IL-1β, have been attributed to autophagy-related factors such as ATG5 and ATG7 [ 3 , 9 ]. During secretion, SNAP23, SNAP29, STX3, and STX4 are utilized as soluble N -ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) on the plasma membrane (PM) [ 10 , 11 ].…”

“…Recently, we identified that extended-synaptotagmin 1 (E-Syt1), an integral membrane protein anchored on the endoplasmic reticulum (ER), is involved in the unconventional secretion of PKCδ and importin α1 [ 9 ]. E-Syts are a conserved family of tethering factors at the ER-PM contact sites for lipid transport [ 13 ].…”

“…Previous studies reported that E-Syt1 acts as a mediator of cell invasion in non-small cell lung cancer [ 17 ]. We also recently identified E-Syt1 as a key factor in the unconventional secretion pathway in liver cancer [ 9 ]. Loss of E-Syt1 has been reported to reduce ER localization of PKCδ in liver cancer cells.…”