Genome-wide CRISPR Screen Identifies Sec31A as a Key Regulator of Alpha Cell Survival

Kimitaka Shibue, Sevim Kahraman, Jorge Ivan Castillo-Quan, Dario F. Jesus, Jiang Hu, Hiroyuki Morita, T. Keith Blackwell, Peng Yi and Rohit N. Kulkarni ()
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Kimitaka Shibue: Harvard Medical School
Sevim Kahraman: Harvard Medical School
Jorge Ivan Castillo-Quan: Harvard Medical School
Dario F. Jesus: Harvard Medical School
Jiang Hu: Harvard Medical School
Hiroyuki Morita: KITANO HOSPITAL
T. Keith Blackwell: Harvard Medical School
Peng Yi: Harvard Medical School
Rohit N. Kulkarni: Harvard Medical School

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Glucagon, secreted by pancreatic alpha cells, is essential for maintaining normal blood glucose levels. In type 1 and advanced type 2 diabetes, alpha cells often fail to respond to low glucose, yet the mechanisms underlying their stress resistance remain unclear. To investigate this, we performed a genome-wide CRISPR screen and identify Sec31A, a gene involved in transporting proteins from the endoplasmic reticulum (ER), as a key regulator of alpha cell survival under stress. We show that loss of Sec31A enhances survival in stressed mouse alpha cells and in C. elegans. In human islets, SEC31A expression increases in alpha cells under inflammatory stress, and this upregulation is reversed by reducing ER stress. Functional studies in lab-grown human islet clusters reveal distinct responses in alpha versus beta cells following Sec31A suppression. We also find that Sec31A interacts with the insulin receptor, suggesting a link between stress adaptation and insulin signaling in alpha cells.

Date: 2025
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DOI: 10.1038/s41467-025-64169-5

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