T-2 Toxin-Mediated β-Arrestin-1 O-GlcNAcylation Exacerbates Glomerular Podocyte Injury via Regulating Histone Acetylation

T-2 toxin causes renal dysfunction with proteinuria and glomerular podocyte damage. This work explores the role of metabolic disorder/reprogramming-mediated epigenetic modification in the progression of T-2 toxin-stimulated podocyte injury. A metabolomics experiment is performed to assess metabolic responses to T-2 toxin infection in human podocytes. Roles of protein O-linked-N-acetylglucosaminylation (O-GlcNAcylation) in regulating T-2 toxin-stimulated podocyte injury in mouse and podocyte models are assessed. O-GlcNAc target proteins are recognized by mass spectrometry and co-immunoprecipitation experiments. Moreover, histone acetylation and autophagy levels are measured. T-2 toxin infection upregulates glucose transporter type 1 (GLUT1) expression and enhances hexosamine biosynthetic pathway in glomerular podocytes, resulting in a significant increase in beta-arrestin-1 O-GlcNAcylation. Decreasing beta-arrestin-1 or O-GlcNAc transferase (OGT) effectively prevents T-2 toxin-induced renal dysfunction and podocyte injury. Mechanistically, O-GlcNAcylation of beta-arrestin-1 stabilizes beta-arrestin-1 to activate the mammalian target of rapamycin (mTOR) pathway as well as to inhibit autophagy during podocyte injury by promoting H4K16 acetylation. To sum up, OGT-mediated beta-arrestin-1 O-GlcNAcylation is a vital regulator in the development of T-2 toxin-stimulated podocyte injury via activating the mTOR pathway to suppress autophagy. Targeting beta-arrestin-1 or OGT can be a potential therapy for T-2 toxin infection-associated glomerular injury, especially podocyte injury.

Automated summary

This study investigates the role of metabolic disorder/reprogramming-mediated epigenetic modification in the progression of T-2 toxin-stimulated podocyte injury. The researchers found that O-GlcNAcylation plays a vital regulatory role in the development of T-2 toxin-stimulated podocyte injury by activating the mTOR pathway to suppress autophagy. Targeting beta-arrestin-1 or OGT could be a potential therapy for T-2 toxin infection-associated glomerular injury, especially podocyte injury.