A role and mechanism for redox sensing by SENP1 in β-cell responses to high fat feeding

Haopeng Lin, Kunimasa Suzuki, Nancy Smith, Xi Li, Lisa Nalbach, Sonia Fuentes, Aliya F. Spigelman, Xiao-Qing Dai, Austin Bautista, Mourad Ferdaoussi, Saloni Aggarwal, Andrew R. Pepper, Leticia P. Roma, Emmanuel Ampofo, Wen-hong Li and Patrick E. MacDonald ()
Additional contact information
Haopeng Lin: University of Alberta
Kunimasa Suzuki: University of Alberta
Nancy Smith: University of Alberta
Xi Li: University of Texas Southwestern Medical Center
Lisa Nalbach: Saarland University
Sonia Fuentes: University of Texas Southwestern Medical Center
Aliya F. Spigelman: University of Alberta
Xiao-Qing Dai: University of Alberta
Austin Bautista: University of Alberta
Mourad Ferdaoussi: University of Alberta
Saloni Aggarwal: University of Alberta
Andrew R. Pepper: University of Alberta
Leticia P. Roma: Saarland University
Emmanuel Ampofo: Saarland University
Wen-hong Li: University of Texas Southwestern Medical Center
Patrick E. MacDonald: University of Alberta

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract Pancreatic β-cells respond to metabolic stress by upregulating insulin secretion, however the underlying mechanisms remain unclear. Here we show, in β-cells from overweight humans without diabetes and mice fed a high-fat diet for 2 days, insulin exocytosis and secretion are enhanced without increased Ca2+ influx. RNA-seq of sorted β-cells suggests altered metabolic pathways early following high fat diet, where we find increased basal oxygen consumption and proton leak, but a more reduced cytosolic redox state. Increased β-cell exocytosis after 2-day high fat diet is dependent on this reduced intracellular redox state and requires the sentrin-specific SUMO-protease-1. Mice with either pancreas- or β-cell-specific deletion of this fail to up-regulate exocytosis and become rapidly glucose intolerant after 2-day high fat diet. Mechanistically, redox-sensing by the SUMO-protease requires a thiol group at C535 which together with Zn+-binding suppresses basal protease activity and unrestrained β-cell exocytosis, and increases enzyme sensitivity to regulation by redox signals.

Date: 2024
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DOI: 10.1038/s41467-023-44589-x

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