RIP2-deficiency induces inflammation in response to SV40 Large T induced genotoxic stress through altered ROS homeostasis

• Published in: Clinical immunology (Orlando, Fla.) Fla.), 2022-05, Vol.238, p.108998-108998, Article 108998
• Main Authors: Kapplusch, Franz, Schulze, Felix, Reinke, Sören, Russ, Susanne, Linge, Mary, Kulling, Franziska, Kriechling, Florian, Höhne, Katrin, Winkler, Stefan, Hartmann, Hella, Rösen-Wolff, Angela, Anastassiadis, Konstantinos, Hedrich, Christian M., Hofmann, Sigrun R.
• Format: Article
• Language: English
• Subjects: DNA damage response; Genotoxic stress; Inflammation; Receptor interacting protein kinase 2; RIP2; SV40 Large T
• ISSN: 1521-6616; 1521-7035
• DOI: 10.1016/j.clim.2022.108998

Deciphering signaling pathways that regulate the complex interplay between inflammation and cell death is a key challenge in understanding innate immune responses. Over recent years, receptor interacting protein (RIP) kinases have been described to regulate the interplay between inflammation and cell death. Whereas RIP1 and 3, the most well described members of the RIP kinase family, play important roles in necroptosis, RIP2's involvement in regulating inflammation, cell death processes and cancer is less well described and controversially discussed. Here, we demonstrate that RIP2 exerts immune regulatory functions by regulating mitochondrial damage and mitochondrial superoxide production in response to SV40 LT-induced genotoxic stress by the induction of ULK1-phosphorylation, therefore regulating the expression of interferon stimulated genes (ISGs) and NLRP3-inflammasome dependent IL-1β release. Because RIP2 is upregulated and/or activated in autoimmune/inflammatory disease and cancer, observations from this study promise implications of RIP kinases in human disease. •SV40 Large T (LT) expression induces genotoxic stress and mitochondrial damage.•RIP2 exerts regulatory effects in response to genotoxic stress regulating mitochondrial damage.•Loss of RIP2 contributes to increased susceptibility of cells to genotoxic stress.•RIP2-deficiency results in the accumulation of damaged mitochondria and ROS.•RIP2-deficiency further increases ROS-induced ISG expression.