Cold-induced FOXO1 nuclear transport aids cold survival and tissue storage

Xiaomei Zhang, Lihao Ge, Guanghui Jin, Yasong Liu, Qingfen Yu, Weizhao Chen, Liang Chen, Tao Dong, Kiyoharu J. Miyagishima, Juan Shen, Jinghong Yang, Guo Lv, Yan Xu, Qing Yang, Linsen Ye, Shuhong Yi, Hua Li, Qi Zhang, Guihua Chen, Wei Liu (), Yang Yang (), Wei Li () and Jingxing Ou ()
Additional contact information
Xiaomei Zhang: Sun Yat-sen University
Lihao Ge: Xinxiang Medical University
Guanghui Jin: Sun Yat-sen University
Yasong Liu: Sun Yat-sen University
Qingfen Yu: The Third Affiliated Hospital of Sun Yat-sen University
Weizhao Chen: Sun Yat-sen University
Liang Chen: Sun Yat-sen University
Tao Dong: Sun Yat-sen University
Kiyoharu J. Miyagishima: National Institutes of Health
Juan Shen: the Third Affiliated Hospital of Sun Yat-sen University
Jinghong Yang: Sun Yat-sen University
Guo Lv: Guangdong province engineering laboratory for transplantation medicine
Yan Xu: the Third Affiliated Hospital of Sun Yat-sen University
Qing Yang: Sun Yat-sen University
Linsen Ye: Sun Yat-sen University
Shuhong Yi: Sun Yat-sen University
Hua Li: Sun Yat-sen University
Qi Zhang: the Third Affiliated Hospital of Sun Yat-sen University
Guihua Chen: Sun Yat-sen University
Wei Liu: the Third Affiliated Hospital of Sun Yat-sen University
Yang Yang: Sun Yat-sen University
Wei Li: National Institutes of Health
Jingxing Ou: Sun Yat-sen University

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Cold-induced injuries severely limit opportunities and outcomes of hypothermic therapies and organ preservation, calling for better understanding of cold adaptation. Here, by surveying cold-altered chromatin accessibility and integrated CUT&Tag/RNA-seq analyses in human stem cells, we reveal forkhead box O1 (FOXO1) as a key transcription factor for autonomous cold adaptation. Accordingly, we find a nonconventional, temperature-sensitive FOXO1 transport mechanism involving the nuclear pore complex protein RANBP2, SUMO-modification of transporter proteins Importin-7 and Exportin-1, and a SUMO-interacting motif on FOXO1. Our conclusions are supported by cold survival experiments with human cell models and zebrafish larvae. Promoting FOXO1 nuclear entry by the Exportin-1 inhibitor KPT-330 enhances cold tolerance in pre-diabetic obese mice, and greatly prolongs the shelf-life of human and mouse pancreatic tissues and islets. Transplantation of mouse islets cold-stored for 14 days reestablishes normoglycemia in diabetic mice. Our findings uncover a regulatory network and potential therapeutic targets to boost spontaneous cold adaptation.

Date: 2024
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DOI: 10.1038/s41467-024-47095-w

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