Researchers reveal that spermidine-mediated acetylhypusination of RIPK1 suppresses necroptosis and insulin resistance, offering potential therapeutic strategies for type 2 diabetes.
By Tarun Sai LomteReviewed by Susha Cheriyedath, M.Sc.Nov 18 2024 New research uncovers how a natural polyamine, spermidine, modifies RIPK1 to block inflammation and metabolic damage, opening doors to innovative diabetes treatments.In a recent study published in the journal Nature Cell Biology, researchers investigated how N-acetyltransferase -mediated post-translational modification, acetylhypusination, regulates insulin sensitivity and necroptosis.
The gene encoding human NAT2 , an ortholog of murine Nat1 , has been reported to mediate insulin sensitivity. hNAT2 and mNAT1 serve as arylamine N-acetyltransferases in the xenobiotic metabolism of exogenous molecules, like aliphatic amines and some drugs. Recent studies indicate that NAT2 acetylates endogenous aliphatic amines, such as spermidine and putrescine.
Further, Nat1 KO MEFs had lower levels of acetylated forms than WT MEFs and had a higher sensitivity to necroptosis and receptor-interacting serine/threonine-protein kinase 1 -dependent apoptosis . However, treatment with spermidine resulted in a dose-dependent reduction in RIPK1 activation in WT and Nat1 KO MEFs.
Next, the team used mass spectrometry to investigate potential hypusination sites in RIPK1 in Nat1 KO and WT MEFs. This identified an acetylhypusination site , ac-hyp-K140, within the kinase domain and hypusination sites in the kinase and intermediate domains. The researchers focused on the K140 site, given that ac-hyp-K140 was ninefold reduced in Nat1 KO MEFs relative to WT MEFs.
Besides, adipocyte hypertrophy was observed after Nat1 deletion. However, this was not observed in mice with genetically inactivated RIPK1, highlighting RIPK1's role in mediating these metabolic defects. Next, the researchers studied the vascular pathology induced by the endothelium-specific Nat1 loss.
Vascular Aging Apoptosis Autophagy Cell Cell Biology Diabetic Nephropathy Gene Global Health Hyperglycemia Inflammation Insulin Insulin Resistance Kidney Kinase Mass Spectrometry Metabolism Model Organisms Necroptosis Nephropathy Obesity Pathology Protein Receptor Research Serine Spectrometry Threonine Type 2 Diabetes
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