Involvement of NOD2 and RIP2 in the activation of 5-lipoxygenase 4244

Abstract

Abstract Description Nucleotide-binding Oligomerization Domain-Containing Protein 2 (NOD2) is a cytosolic peptidoglycan receptor important for immune defense and homeostasis. Binding muramyl dipeptide (MDP) allows NOD2 to promote the activation of Receptor-Interacting Serine/Threonine Protein Kinase 2 (RIPK2 or RIP2) which transduces downstream signals leading to Nuclear Factor Kappa B (NF-kB) and MAPK activation and pro-inflammatory cytokine release. Due to the known dysregulation of NOD2 signaling in various inflammatory diseases, there has been a lot of interest in pharmacological targeting of this pathway through inhibition of RIP2. Using an MDP peritonitis model, we find that activation of NOD2 also leads to the production of both pro-inflammatory as well as pro-resolution lipid mediators, suggesting an underappreciated arm of NOD2/RIP2 signaling and a potential role for NOD2 and RIP2 in resolution biology. Mechanistically, we demonstrate that RIP2 promoted the phosphorylation and enzymatic activation of Arachidonate 5-Lipoxygenase (5LO), an enzyme important for lipid mediator production. The consequences of disrupting the interaction between RIP2 and XIAP and of pharmacologic inhibition of RIP2, on 5LO activation was also assessed. This work will uncover mechanisms unique to either NF-kB activation, or this novel arm of 5LO activation. Additionally, this could guide the development of therapies for targeting one or both signaling arms, with important consequences for drug efficacy. Funding Sources This work was supported through NSF CAREER 2338587 awarded to J.T.T-A. Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)