The death domain containing serine/threonine kinase Ripk1 is the core component of TNF-induced signaling complexes mediating NF?B and MAP kinase activation, apoptosis and an alternative form of caspase independent cell death called necroptosis. In unbiased genome wide siRNA screens for regulators of necroptosis, Ripk1, its deubiquitinase Cyld, the related Ripk3 as well as other proteins belonging to the interferon and Toll-like receptor signaling systems were identified. These studies and those using an allosteric Ripk1 kinase inhibitor or Ripk3-deficient mice establish necroptosis as a prominent host defense against viral infection. Necroptosis requires the kinase activities of Ripk1 and Ripk3 but precisely how Rip kinases initiate and execute necroptotic cell death is unknown. We have shown that Ripk1 has additional signaling functions beyond TNF, in nucleic acid sensing pathways mediated by TLR3 and Rig-I. Our preliminary studies additionally implicate Ripk1 in a cytosolic DNA sensing pathway involving Sting, Tbk1 and Irf3. Collectively, these studies predict a central role for Ripk1 in innate anti-viral immunity, however the perinatal lethality associated with a Ripk1-deficiency has precluded in vivo analyses. Goals of the current proposal are to test a requirement for Ripk1 in the anti-viral innate immune response using the conditional Ripk1 mice we have generated. We have also introduced a mutation into the Ripk1 locus that impairs the kinase activity of Ripk1. Our preliminary studies in Ripk1 kinase inactive MEFs and macrophages find these cells protected from TNF- and TLR3-induced necroptosis, respectively. An additional objective of this proposal is to examine the contribution of viral-initiated necroptosis to host defense in these newly engineered Ripk1 kinase inactive mice. In addition to virus-induced injury and inflammation, Rip kinases respond to non-microbial signals called danger-associated molecular patterns (DAMPs) released upon tissue injury. The long-term goal of these studies is to selectively inhibit Rip kinases in sterile inflammation without impairing innate immunity.
This proposal examines the role of the serine/threonine kinase Ripk1 in host defense to viral infection. The kinase activity of Ripk1 is required for a for of cell death called necroptosis, used by the host to limit viral replication and activate immune cells. We plan to infect the new mouse Ripk1 models we have generated with RNA and DNA viruses and analyze viral replication, cytokine production and adaptive immune responses.
|Zelic, Matija; Roderick, Justine E; O'Donnell, Joanne A et al. (2018) RIP kinase 1-dependent endothelial necroptosis underlies systemic inflammatory response syndrome. J Clin Invest 128:2064-2075|
|Orning, Pontus; Weng, Dan; Starheim, Kristian et al. (2018) Pathogen blockade of TAK1 triggers caspase-8-dependent cleavage of gasdermin D and cell death. Science 362:1064-1069|
|O'Donnell, Joanne A; Lehman, Jesse; Roderick, Justine E et al. (2018) Dendritic Cell RIPK1 Maintains Immune Homeostasis by Preventing Inflammation and Autoimmunity. J Immunol 200:737-748|
|Saleh, Danish; Najjar, Malek; Zelic, Matija et al. (2017) Kinase Activities of RIPK1 and RIPK3 Can Direct IFN-? Synthesis Induced by Lipopolysaccharide. J Immunol 198:4435-4447|
|Vlantis, Katerina; Wullaert, Andy; Polykratis, Apostolos et al. (2016) NEMO Prevents RIP Kinase 1-Mediated Epithelial Cell Death and Chronic Intestinal Inflammation by NF-?B-Dependent and -Independent Functions. Immunity 44:553-567|
|Ito, Yasushi; Ofengeim, Dimitry; Najafov, Ayaz et al. (2016) RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS. Science 353:603-8|
|Najjar, Malek; Saleh, Danish; Zelic, Matija et al. (2016) RIPK1 and RIPK3 Kinases Promote Cell-Death-Independent Inflammation by Toll-like Receptor 4. Immunity 45:46-59|
|Legarda, Diana; Justus, Scott J; Ang, Rosalind L et al. (2016) CYLD Proteolysis Protects Macrophages from TNF-Mediated Auto-necroptosis Induced by LPS and Licensed by Type I IFN. Cell Rep 15:2449-61|
|Kondylis, Vangelis; Polykratis, Apostolos; Ehlken, Hanno et al. (2015) NEMO Prevents Steatohepatitis and Hepatocellular Carcinoma by Inhibiting RIPK1 Kinase Activity-Mediated Hepatocyte Apoptosis. Cancer Cell 28:582-598|
|El-Assaad, Wissal; El-Kouhen, Karim; Mohammad, Amro H et al. (2015) Deletion of the gene encoding G0/G 1 switch protein 2 (G0s2) alleviates high-fat-diet-induced weight gain and insulin resistance, and promotes browning of white adipose tissue in mice. Diabetologia 58:149-57|
Showing the most recent 10 out of 21 publications