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

Author

Listed:
  • Kimitaka Shibue

    (Harvard Medical School
    KITANO HOSPITAL)

  • 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
    Harvard Stem Cell Institute)

  • Peng Yi

    (Harvard Medical School)

  • Rohit N. Kulkarni

    (Harvard Medical School
    Harvard Stem Cell Institute)

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.

Suggested Citation

  • Kimitaka Shibue & Sevim Kahraman & Jorge Ivan Castillo-Quan & Dario F. Jesus & Jiang Hu & Hiroyuki Morita & T. Keith Blackwell & Peng Yi & Rohit N. Kulkarni, 2025. "Genome-wide CRISPR Screen Identifies Sec31A as a Key Regulator of Alpha Cell Survival," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-64169-5
    DOI: 10.1038/s41467-025-64169-5
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    References listed on IDEAS

    as
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