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  3. Spermidine mediates acetylhypusination of RIPK1 to suppress diabetes onset and progression

Spermidine mediates acetylhypusination of RIPK1 to suppress diabetes onset and progression

  • Nat Cell Biol. 2024 Dec;26(12):2099-2114. doi: 10.1038/s41556-024-01540-6.
Tian Zhang 1 2,  Weixin Fu 1 3,  Haosong Zhang 1 2,  Jianlong Li 1 2,  Beizi Xing 1 2,  Yuping Cai 1,  Mengmeng Zhang 1,  Xuheng Liu 1 2,  Chunting Qi 1,  Lihui Qian 1,  Xinbo Hu 1,  Hua Zhu 1,  Shuailong Yang 1 2,  Min Zhang 1 2,  Jianping Liu 1,  Ganquan Li 1 2,  Yang Li 1 2,  Rong Xiang 1,  Zhengqiang Qi 1,  Junhao Hu 1,  Ying Li 1,  Chengyu Zou 1 4,  Qin Wang 5,  Xia Jin 6,  Rui Pang 6 7,  Peiying Li 6 7,  Junli Liu 8,  Yaoyang Zhang 1 4,  Zhaoyin Wang 1,  Zheng-Jiang Zhu 9 10,  Bing Shan 11,  Junying Yuan 12 13
Affiliations

Affiliations

  • 1 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.
  • 2 University of Chinese Academy of Sciences, Beijing, China.
  • 3 Nankai University, Tianjin, China.
  • 4 Shanghai Key Laboratory of Aging Studies, Shanghai, China.
  • 5 Department of Nephrology, Molecular Cell Lab for Kidney Disease, Shanghai Peritoneal Dialysis Research Center, Renji Hospital, Uremia Diagnosis and Treatment Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 6 Department of Anesthesiology, Key Laboratory of the Ministry of Education, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 7 Clinical Research Center, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 8 Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 9 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China. jiangzhu@sioc.ac.cn.
  • 10 Shanghai Key Laboratory of Aging Studies, Shanghai, China. jiangzhu@sioc.ac.cn.
  • 11 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China. shanbing@sioc.ac.cn.
  • 12 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China. junying_yuan@sioc.ac.cn.
  • 13 Shanghai Key Laboratory of Aging Studies, Shanghai, China. junying_yuan@sioc.ac.cn.
PMID: 39511379 DOI: 10.1038/s41556-024-01540-6
Abstract

It has been established that N-acetyltransferase (murine NAT1 (mNAT1) and human NAT2 (hNAT2)) mediates Insulin sensitivity in type 2 diabetes. Here we show that mNAT1 deficiency leads to a decrease in cellular spermidine-a natural polyamine exhibiting health-protective and anti-ageing effects-but understanding of its mechanism is limited. We identify that mNAT1 and hNAT2 modulate a type of post-translational modification involving acetylated spermidine, which we name acetylhypusination, on receptor-interacting serine/threonine-protein kinase 1 (RIPK1)-a key regulator of inflammation and cell death. Spermidine supplementation decreases RIPK1-mediated cell death and diabetic phenotypes induced by NAT1 deficiency in vivo. Furthermore, Insulin resistance and diabetic kidney disease mediated by vascular pathology in NAT1-deficient mice can be blocked by inhibiting RIPK1. Finally, we demonstrate a decrease in spermidine and activation of RIPK1 in the vascular tissues of human patients with diabetes. Our study suggests a role for vascular pathology in diabetes onset and progression and identifies the inhibition of RIPK1 kinase as a potential therapeutic approach for the treatment of type 2 diabetes.

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