Scholarlink

<p>Glucagon, secreted by pancreatic alpha cells, is essential for maintaining&#xa0;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&#xa0; their stress resistance remain unclear. To investigate this, we performed a genome-wide CRISPR screen and identify <i>Sec31A</i>, 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 <i>Sec31A</i> enhances survival in stressed mouse alpha cells and in <i>C. elegans</i>. In human islets, <i>SEC31A</i> 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 <i>Sec31A</i> suppression. We also find that <i>Sec31A</i> interacts with the insulin receptor, suggesting a link between stress adaptation and insulin signaling in alpha cells.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年10月15日

查看全文
  • Kimitaka Shibue,
  • Sevim Kahraman,
  • Jorge Ivan Castillo-Quan,
  • Dario F. De Jesus,
  • Jiang Hu,
  • Hiroyuki Morita,
  • T. Keith Blackwell,
  • Peng Yi,
  • Rohit N. Kulkarni

摘要

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.