March5-mediated Trim28 degradation preserves islet β-cell function in mice

Yangshan Chen, Wei Pang, Guixing Ma (), Yongcong Yan, Zhiyu Xiao, Yong Chen, Zhen Ding, Litong Chen, Xiaoting Hou and Huiling Cao ()
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Yangshan Chen: Southern University of Science and Technology
Wei Pang: Southern University of Science and Technology
Guixing Ma: Southern University of Science and Technology
Yongcong Yan: Sun Yat-Sen University
Zhiyu Xiao: Sun Yat-Sen University
Yong Chen: Southern University of Science and Technology
Zhen Ding: Southern University of Science and Technology
Litong Chen: Southern University of Science and Technology
Xiaoting Hou: Southern University of Science and Technology
Huiling Cao: Southern University of Science and Technology

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract Insulin deficiency from β-cell dysfunction underpins both type 1 and type 2 diabetes. However, the regulatory pathways underlying β-cell function remain incompletely understood. Here, we identify that March5 and Trim28 as key modulators of β-cell function. March5 is downregulated and Trim28 upregulated in islets from human or mouse with impaired glucose tolerance. Loss of March5 in β-cells impairs insulin production and glucose tolerance, while its overexpression improves both. Mechanistically, March5 inhibits Trim28 by targeting it for ubiquitination, thereby preventing Trim28-mediated Kindlin-2 degradation, which elevates MafA and insulin expression in male mice. Trim28 deletion in β-cells rescues glucose intolerance in March5-deficient male mice, highlighting their joint regulatory pathway. Furthermore, March5 and Kindlin-2 double haploinsufficiency significantly impair insulin production and glucose tolerance, underscoring their shared pathway. Importantly, islet transplantation with March5-overexpressing or Trim28-deficient β-cells effectively ameliorates glucose intolerance in streptozotocin-induced diabetic male mice. In conclusion, our results suggest that targeting the March5/Trim28/Kindlin-2/MafA pathway may offer a promising therapeutic strategy to restore β-cell function in diabetes.

Date: 2025
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DOI: 10.1038/s41467-025-62587-z

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