SUMOylation and calcium control syntaxin-1A and secretagogin sequestration by tomosyn to regulate insulin exocytosis in human ß cells.
Insulin secretion from pancreatic ß cells is a multistep process that requires the coordination of exocytotic proteins that integrate diverse signals. These include signals derived from metabolic control of post-translational SUMOylation and depolarization-induced rises in intracellular Ca2+. Here we show that tomosyn, which suppresses insulin exocytosis by binding syntaxin1A, does so in a manner which requires its SUMOylation. Glucose-dependent de-SUMOylation of tomosyn1 at K298 releases syntaxin1A and controls the amplification of exocytosis in concert with a recently-identified tomosyn1-interacting partner; the Ca2+-binding protein secretagogin, which dissociates from tomosyn1 in response to Ca2+-raising stimuli and is required for insulin granule trafficking and exocytosis downstream of Ca2+influx. Together our results suggest that tomosyn acts as a key signaling hub in insulin secretion by integrating signals mediated by metabolism-dependent de-SUMOylation and electrically-induced entry of Ca2+to regulate the availability of exocytotic proteins required for the amplification of insulin secretion.
Alberta Diabetes Institute and Department of Pharmacology, University of Alberta, Edmonton, Alberta, T6G 2R3, Canada. ferdaous@ualberta.ca.
Mourad
M
Ferdaoussi
Alberta Diabetes Institute and Department of Pharmacology, University of Alberta, Edmonton, Alberta, T6G 2R3, Canada.
Jianyang
J
Fu
Alberta Diabetes Institute and Department of Pharmacology, University of Alberta, Edmonton, Alberta, T6G 2R3, Canada.
Xiaoqing
X
Dai
Alberta Diabetes Institute and Department of Pharmacology, University of Alberta, Edmonton, Alberta, T6G 2R3, Canada.
Jocelyn E
JE
Manning Fox
Alberta Diabetes Institute and Department of Pharmacology, University of Alberta, Edmonton, Alberta, T6G 2R3, Canada.
Kunimasa
K
Suzuki
Alberta Diabetes Institute and Department of Pharmacology, University of Alberta, Edmonton, Alberta, T6G 2R3, Canada.
Nancy
N
Smith
Alberta Diabetes Institute and Department of Pharmacology, University of Alberta, Edmonton, Alberta, T6G 2R3, Canada.
Gregory
G
Plummer
Alberta Diabetes Institute and Department of Pharmacology, University of Alberta, Edmonton, Alberta, T6G 2R3, Canada. pmacdonald@ualberta.ca.
Patrick E
PE
MacDonald
D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D005089:Exocytosis; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D050683:R-SNARE Proteins / Q000378:metabolism*; D064046:Secretagogins / Q000378:metabolism*; D058207:Sumoylation; D050827:Syntaxin 1 / Q000378:metabolism*
D007328:Insulin; D009419:Nerve Tissue Proteins; D050683:R-SNARE Proteins; C576556:SCGN protein, human; C484767:STXBP5 protein, human; D064046:Secretagogins; D050827:Syntaxin 1; D002118:Calcium