Spermidine mediates acetylhypusination of RIPK1 to suppress diabetes onset and progression

Nature Cell Biology. (2024)

Affiliations

Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China
University of Chinese Academy of Sciences, Beijing, China
Nankai University, Tianjin, China
Shanghai Key Laboratory of Aging Studies, Shanghai, China
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
Department of Anesthesiology, Key Laboratory of the Ministry of Education, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Clinical Research Center, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China

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.

研究已表明，N-乙酰转移酶（鼠源NAT1（mNAT1）和人源NAT2（hNAT2））在2型糖尿病的胰岛素敏感性中起到重要作用。在本研究中，我们发现mNAT1缺失会导致细胞中天然多胺——亚精胺的减少，而亚精胺具有健康保护和抗衰老的作用，但其作用机制仍不清楚。我们发现mNAT1和hNAT2调控了一种涉及乙酰化亚精胺的翻译后修饰，我们将其命名为乙酰羟丁胺修饰（acetylhypusination），该修饰作用于受体相互作用丝氨酸/苏氨酸蛋白激酶1（RIPK1），而RIPK1是炎症和细胞死亡的关键调节因子。补充亚精胺能够降低RIPK1介导的细胞死亡，并缓解体内因NAT1缺失引起的糖尿病表型。此外，通过抑制RIPK1可以阻止NAT1缺失小鼠因血管病变引起的胰岛素抵抗和糖尿病肾病。最后，我们在糖尿病患者的血管组织中观察到亚精胺减少和RIPK1的活化。我们的研究提示血管病变在糖尿病的发病和进展中可能起到作用，并且RIPK1激酶的抑制可作为2型糖尿病治疗的潜在方法。

关键词：NAT1，亚精胺，糖尿病，RIPK1激酶，乙酰羟丁胺修饰，acetylhypusination，RGK08108，Anti-Hypusine antibody (Hpu24)，佰乐博，佰乐博生物