title: Septin 7 reduces nonmuscle myosin IIA activity in the SNAP23 complex and hinders GLUT4 storage vesicle docking and fusion.
abstract: Glomerular epithelial cells, podocytes, are insulin responsive and can develop insulin resistance. Here, we demonstrate that the small GTPase septin 7 forms a complex with nonmuscle myosin heavy chain IIA (NMHC-IIA; encoded by MYH9), a component of the nonmuscle myosin IIA (NM-IIA) hexameric complex. We observed that knockdown of NMHC-IIA decreases insulin-stimulated glucose uptake into podocytes. Both septin 7 and NM-IIA associate with SNAP23, a SNARE protein involved in GLUT4 storage vesicle (GSV) docking and fusion with the plasma membrane. We observed that insulin decreases the level of septin 7 and increases the activity of NM-IIA in the SNAP23 complex, as visualized by increased phosphorylation of myosin regulatory light chain. Also knockdown of septin 7 increases the activity of NM-IIA in the complex. The activity of NM-IIA is increased in diabetic rat glomeruli and cultured human podocytes exposed to macroalbuminuric sera from patients with type 1 diabetes. Collectively, the data suggest that the activity of NM-IIA in the SNAP23 complex plays a key role in insulin-stimulated glucose uptake into podocytes. Furthermore, we observed that septin 7 reduces the activity of NM-IIA in the SNAP23 complex and thereby hinders GSV docking and fusion with the plasma membrane.
authors.affiliation: Department of Pathology, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Anita A
authors.initials: AA
authors.lastname: Wasik
authors.affiliation: Department of Pathology, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Vincent
authors.initials: V
authors.lastname: Dumont
authors.affiliation: Department of Pathology, University of Helsinki and Helsinki University Hospital, 00290 Helsinki, 05850 Hyvinkää, Finland.
authors.forename: Jukka
authors.initials: J
authors.lastname: Tienari
authors.affiliation: Institute of Biotechnology, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Tuula A
authors.initials: TA
authors.lastname: Nyman
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, 00290 Helsinki, Finland; Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, 000290 Helsinki, Finland; Diabetes&Obesity Research Program, Research Program´s Unit, 00014 University of Helsinki, Finland.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Fogarty
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, 00290 Helsinki, Finland; Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, 000290 Helsinki, Finland; Diabetes&Obesity Research Program, Research Program´s Unit, 00014 University of Helsinki, Finland.
authors.forename: Carol
authors.initials: C
authors.lastname: Forsblom
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, 00290 Helsinki, Finland; Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, 000290 Helsinki, Finland; Diabetes&Obesity Research Program, Research Program´s Unit, 00014 University of Helsinki, Finland.
authors.forename: Markku
authors.initials: M
authors.lastname: Lehto
authors.affiliation: Department of Pathology, University of Helsinki, 00014 Helsinki, Finland; Laboratory Animal Centre, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Eero
authors.initials: E
authors.lastname: Lehtonen
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, 00290 Helsinki, Finland; Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, 000290 Helsinki, Finland; Diabetes&Obesity Research Program, Research Program´s Unit, 00014 University of Helsinki, Finland; Baker IDI Heart & Diabetes Institute, 3004 Melbourne, Australia.
authors.forename: Per-Henrik
authors.initials: PH
authors.lastname: Groop
authors.affiliation: Department of Pathology, University of Helsinki, 00014 Helsinki, Finland. Electronic address: sanna.h.lehtonen@helsinki.fi.
authors.forename: Sanna
authors.initials: S
authors.lastname: Lehtonen
mesh_terms: D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007684:Kidney Tubules / Q000378:metabolism; D051379:Mice; D024507:Nonmuscle Myosin Type IIA / Q000378:metabolism*; D050199:Podocytes / Q000378:metabolism; D051381:Rats; D058112:Septins / Q000235:genetics / Q000378:metabolism*; D022161:Transport Vesicles / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000378:metabolism*
chemical_list: D051275:Glucose Transporter Type 4; D007328:Insulin; D033921:Vesicular Transport Proteins; D024507:Nonmuscle Myosin Type IIA; D058112:Septins; D005947:Glucose
keywords: GLUT4 storage vesicle; Glucose uptake; Nonmuscle myosin IIA; Podocytes; SNARE; Septin 7