The role of receptor interacting protein kinase 3 in inflammatory signalling

Inflammatory signalling and programmed cell death are fundamental processes employed by higher order organisms as defence mechanisms against foreign substances. Necroptosis, a proinflammatory type of programmed cell death mediated by the kinase RIPK3, has emerged as an important innate immune defence mechanism against viruses. The necroptosis process is accompanied by de novo synthesis of cytokines and chemokines within the dying cells. However, how inflammatory signalling is induced in the necroptotic cell remains poorly understood. In this study, I describe that RIPK3, independently of its cell death-inducing activity, stimulates inflammatory signalling pathways mediated by the kinases TAK1 and IKKs. I provide evidence that RIPK3 can stimulate inflammatory signalling through two distinct mechanisms, the scaffolding-dependent pathway and the RIPK3 kinase activity-dependent pathway. In the scaffolding-dependent pathway, RIPK1 connects RIPK3 to the ubiquitin ligases, cIAPs and LUBAC, for the activation of TAK1 and IKKs through K63- and M1-linked polyubiquitin, independent of RIPK3’s kinase activity. In contrast, the RIPK3 kinase activity-dependent pathway does not require cIAPs or LUBAC, but is mediated by RIPK3’s kinase activity and its substrate, MLKL, and is suppressed by the RIPK1-recruited protease caspase-8. Taken together, this study indicates that RIPK3, like its family members RIPK1 and RIPK2, is a scaffolding kinase able to promote inflammatory signalling. RIPK3 promotes inflammatory signalling through kinase-dependent and -independent mechanisms. Given the role of necroptosis in the host defence against viruses that often encode caspase inhibitors, RIPK3 kinase activity-dependent signalling may serve not only as an additional mechanism to ensure the activation of inflammatory signalling, but also as a regulatory checkpoint between RIPK3-mediated inflammatory signalling and cell death.