Inflammation is the initial response of the immune system to invading microbes or tissue damage Inflammation aims to remove cause of infection/damage and initiate the healing process However, uncontrolled inflammation can be self-destructive and underlies several pathologies Recently, it was found that deregulated TNF-mediated RIPK1-dependent cell death contributes to inflammation by disrupting epithelial barriers and/or by releasing danger signals into the extracellular environment However, the exact role of the RIPK1 kinase acitvity in cell death is unknown Indeed, no RIPK1 substrates have been identified yet This project aims to identify RIPK1 prodeath substrates via an integrative approach of several proteome-wide approaches This will allow to filter out putative direct RIPK1 prodeath substrates from the vast amount of data generated Biochemical and cellular assays will then be done with cells expressing phosphomimetic or phosphodeficient RIPK1 substrate mutants to elucidate the action mechanism of the substrate and to study how phosphorylation by RIPK1 affects the substrate’ activity Finally, we will generate new tools, phosphospecific antibodies and a phosphomutant substrate knockin mouse line, to study the in vivo relevance of the phosphorylation of this substrate by RIPK1