{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Wang S"],"funding":["NIDDK NIH HHS","NIA NIH HHS","NIGMS NIH HHS"],"pagination":["636-646"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC7971124"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["21(10)"],"pubmed_abstract":["Exocytosis is a vesicle fusion process driven by soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs). A classic exocytic pathway is insulin-stimulated translocation of the glucose transporter type 4 (GLUT4) from intracellular vesicles to the plasma membrane in adipocytes and skeletal muscles. The GLUT4 exocytic pathway plays a central role in maintaining blood glucose homeostasis and is compromised in insulin resistance and type 2 diabetes. A candidate regulator of GLUT4 exocytosis is tomosyn, a soluble protein expressed in adipocytes. Tomosyn directly binds to GLUT4 exocytic SNAREs in vitro but its role in GLUT4 exocytosis was unknown. In this work, we used CRISPR-Cas9 genome editing to delete the two tomosyn-encoding genes in adipocytes. We observed that both basal and insulin-stimulated GLUT4 exocytosis was markedly elevated in the double knockout (DKO) cells. By contrast, adipocyte differentiation and insulin signaling remained intact in the DKO adipocytes. In a reconstituted liposome fusion assay, tomosyn inhibited all the SNARE complexes underlying GLUT4 exocytosis. The inhibitory activity of tomosyn was relieved by NSF and α-SNAP, which act in concert to remove tomosyn from GLUT4 exocytic SNAREs. Together, these studies revealed an inhibitory role for tomosyn in insulin-stimulated GLUT4 exocytosis in adipocytes. We suggest that tomosyn-arrested SNAREs represent a reservoir of fusion capacity that could be harnessed to treat patients with insulin resistance and type 2 diabetes."],"journal":["Traffic (Copenhagen, Denmark)"],"pubmed_title":["Genetic evidence for an inhibitory role of tomosyn in insulin-stimulated GLUT4 exocytosis."],"pmcid":["PMC7971124"],"funding_grant_id":["R35 GM126960","RF1 AG061829","R01 DK124431"],"pubmed_authors":["Wan C","Liu Y","Shen J","Crisman L","Wang S","Miller J","Yu H"],"additional_accession":[]},"is_claimable":false,"name":"Genetic evidence for an inhibitory role of tomosyn in insulin-stimulated GLUT4 exocytosis.","description":"Exocytosis is a vesicle fusion process driven by soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs). A classic exocytic pathway is insulin-stimulated translocation of the glucose transporter type 4 (GLUT4) from intracellular vesicles to the plasma membrane in adipocytes and skeletal muscles. The GLUT4 exocytic pathway plays a central role in maintaining blood glucose homeostasis and is compromised in insulin resistance and type 2 diabetes. A candidate regulator of GLUT4 exocytosis is tomosyn, a soluble protein expressed in adipocytes. Tomosyn directly binds to GLUT4 exocytic SNAREs in vitro but its role in GLUT4 exocytosis was unknown. In this work, we used CRISPR-Cas9 genome editing to delete the two tomosyn-encoding genes in adipocytes. We observed that both basal and insulin-stimulated GLUT4 exocytosis was markedly elevated in the double knockout (DKO) cells. By contrast, adipocyte differentiation and insulin signaling remained intact in the DKO adipocytes. In a reconstituted liposome fusion assay, tomosyn inhibited all the SNARE complexes underlying GLUT4 exocytosis. The inhibitory activity of tomosyn was relieved by NSF and α-SNAP, which act in concert to remove tomosyn from GLUT4 exocytic SNAREs. Together, these studies revealed an inhibitory role for tomosyn in insulin-stimulated GLUT4 exocytosis in adipocytes. We suggest that tomosyn-arrested SNAREs represent a reservoir of fusion capacity that could be harnessed to treat patients with insulin resistance and type 2 diabetes.","dates":{"release":"2020-01-01T00:00:00Z","publication":"2020 Oct","modification":"2025-04-04T12:31:56.766Z","creation":"2025-04-04T12:31:56.766Z"},"accession":"S-EPMC7971124","cross_references":{"pubmed":["32851733"],"doi":["10.1111/tra.12760"]}}