Talin-1 inhibits Smurf1-mediated Stat3 degradation to modulate β-cell proliferation and mass in mice.
Talin-1 inhibits Smurf1-mediated Stat3 degradation to modulate β-cell proliferation and mass in mice.
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DOI：
10.1038/s41419-023-06235-8
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发表时间：
2023-10-31
影响因子：
9
通讯作者：
Cao, Huiling
中科院分区：
文献类型：
--
作者：
Hou, Xiaoting;Chen, Yangshan;Zhou, Bo;Tang, Wanze;Ding, Zhen;Chen, Litong;Wu, Yun;Yang, Hongyu;Du, Changzheng;Yang, Dazhi;Ma, Guixing;Cao, Huiling
胰腺β细胞质量不足和胰岛素表达降低是糖尿病（DM）发病机制中的关键事件。在这里，我们证明了Talin-1在β细胞中的高表达，并且Talin-1的缺乏减少了β细胞增殖，这导致β细胞质量和胰岛素表达减少，从而导致葡萄糖耐受不良，而不影响小鼠的外周胰岛素敏感性。高脂饲料喂养表现出这些表型。在机制上，Talin-1与E3连接酶smad泛素化调节因子1（Smurf 1）相互作用，其抑制由Smurf 1介导的信号转导子和转录激活子3（Stat 3）的泛素化，并且Talin-1的消融增强Smurf 1介导的Stat 3的泛素化，导致β细胞增殖和质量降低。此外，小鼠β细胞中Talin-1和Stat 3基因的单倍不足，而不是任一基因的单倍不足，显著损害葡萄糖耐量和胰岛素表达，表明这两种因子确实在相同的遗传途径中起作用。最后，β细胞中Talin-1的可诱导缺失导致成年小鼠的葡萄糖耐受不良。总的来说，我们的研究结果揭示了Talin-1作为β细胞质量的关键调节剂发挥作用，并突出了其作为DM患者治疗靶点的潜力。
Insufficient pancreatic β-cell mass and reduced insulin expression are key events in the pathogenesis of diabetes mellitus (DM). Here we demonstrate the high expression of Talin-1 in β-cells and that deficiency of Talin-1 reduces β-cell proliferation, which leads to reduced β-cell mass and insulin expression, thus causing glucose intolerance without affecting peripheral insulin sensitivity in mice. High-fat diet fed exerbates these phenotypes. Mechanistically, Talin-1 interacts with the E3 ligase smad ubiquitination regulatory factor 1 (Smurf1), which prohibits ubiquitination of the signal transducer and activator of transcription 3 (Stat3) mediated by Smurf1, and ablation of Talin-1 enhances Smurf1-mediated ubiquitination of Stat3, leading to decreased β-cell proliferation and mass. Furthermore, haploinsufficiency of Talin-1 and Stat3 genes, but not that of either gene, in β-cell in mice significantly impairs glucose tolerance and insulin expression, indicating that both factors indeed function in the same genetic pathway. Finally, inducible deletion Talin-1 in β-cell causes glucose intolerance in adult mice. Collectively, our findings reveal that Talin-1 functions as a crucial regulator of β-cell mass, and highlight its potential as a therapeutic target for DM patients.
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影响因子：
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作者：
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