| First Author | Zhang T | Year | 2024 |
| Journal | Nat Cell Biol | Volume | 26 |
| Issue | 12 | Pages | 2099-2114 |
| PubMed ID | 39511379 | Mgi Jnum | J:360139 |
| Mgi Id | MGI:7797662 | Doi | 10.1038/s41556-024-01540-6 |
| Citation | Zhang T, et al. (2024) Spermidine mediates acetylhypusination of RIPK1 to suppress diabetes onset and progression. Nat Cell Biol 26(12):2099-2114 |
| abstractText | 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. |
