Maresin-2 Fine-tunes ULK1 O-GlcNAcylation to Improve Post Myocardial Infarction Remodeling

Abstract

Maresin-2, a specialized pro-solving mediator of inflammation has been consolidated to be a novel cytokine fine-tuning inflammatory cascade. However, the underlying molecular basis is still largely unknown. Focused on cardiac dysfunction and remodeling, we employed in vivo- and in vitro- based genome editing methodology tools including adenosine associated virus, adenosine virus, lenti-virus, plasmid transfection, and CRISPR-Cas9 methodology for investigation. As suggested, exogenous maresin-2 supplement facilitated autophagosome formation by microtubule-associated proteins 1A/1B light chain 3B (LC3) conjugation system under the modulation of O-GlcNAcylation dependent ULK1 activation, whereas reversed by ULK1 S409A and S422A mutagenesis, showcasing the potential O-GlcNAc (O-linked {beta}- N-acetylglucosamine) modifiable sites on ULK1. Moreover, we found that hereafter maresin-2 treatment glutamine-fructose-6-phosphate aminotransferase 1 (GFAT1) which is accessary to sense hexosamine biosynthesis influx is more likely the prime checkpoint for conjugating O-terminal {beta}-N-acetylglucosamine motif onto ULK1, rather than O-linked N-acetylglucosaminyltransferase (OGT). Mechanistically, maresin-2 largely prohibits transforming growth factor-{beta} (TGF-{beta})-activated kinase 1 (TAK1), therefore increasing the availability of TAB1 for GFAT1, which encourages O-GlcNAcylation of ULK1.