The nucleoporin RanBP2 is a component of the cytoplasmic filaments of the nuclear pore complex known to regulate the nuclear export of RNA molecules, and the post-translational modification of proteins during nucleocytoplasmic trafficking. Mutations in the N-terminal domain of RanBP2 are associated with a rare genetic predisposition in otherwise healthy individuals to deleterious inflammation and Acute Necrotizing Encephalopathy (ANE) following viral infection, frequently by Influenza A virus (IAV). We found that loss of RanBP2 leads to increased expression of some pro-inflammatory cytokines in cell lines and primary immune cells, suggesting that some inflammatory pathways are regulated by RanBP2 and that this control is lost with mutant ANE-associated RanBP2. To uncover the mechanisms linking RanBP2 to deleterious inflammation following IAV infection, we will study both cells lacking RanBP2, and ANE cells that contain the prevalent RanBP2 mutation T585M (c. 1880C/T). Our project aims to establish how RanBP2 regulates the inflammatory response to infection in genetically edited cell lines and mouse models, as well as samples from ANE patients, focusing on (i) the Impact of viral infection, cell type and mutations on RanBP2 localisation and dynamics, (ii) the effect of RanBP2 on cytokine production, and (iii) the CNS-specific role of RanBP2 and brain susceptibility of ANE. The project leverages our diverse expertise in virus/host cell interaction and neuroinflammation. Thus, this collaboration will foster exchange of knowledge, and will help understand how alterations in the nuclear pore complex contribute to disease development following viral infection.