The proposed research project aims at revealing and characterizing the physiological role of MAGED1, a member of the enigmatic melanoma antigen gene (MAGE) family, in the regulation of the inflammatory response. Ubiquitylation plays crucial roles in activating and limiting various levels of innate immune and inflammatory pathways, and several lines of evidence (including preliminary data) indicate that MAGED1 could regulate inflammation by modulating the E3 ubiquitin ligase activity of members of the inhibitor of apoptosis (IAP) and tripartite motif-containing (TRIM) protein families. In order to challenge this hypothesis, the proposed work plan integrates the biochemical characterization of the MAGED1/E3-ubiquitin ligase complexes, the screen for new interacting partners, the identification of pattern recognition receptors (PRRs) and tumor necrosis factor receptors (TNFRs) signaling pathways regulated by MAGED1, and the in vivo validation of the findings obtained in vitro using MAGED1-deficient mice in different mouse model of disease.