The physiological and pathophysiological role of iRhom-2

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iRhom2 is a catalytically inactive member of the rhomboid protease family. The involvement of iRhoms in endoplasmic reticulum trafficking has been described. Our new data shows that iRhom2 interacts with the TNF alpha converting enzyme (TACE/ADAM17) regulating its trafficking and activation. Accordingly, iRhom2 triggers inflammation by regulation of TNF alpha secretion. Consistently, iRhom2 deficient mice survive lethal lipopolysaccharide (LPS) injection and succumb to bacterial infection. However the broader role of iRhom2 during infection and autoimmunity remains unclear. The proposed project will analyze the hypothesis that iRhom2 is a central regulator of immune cells, but not of other parenchymal cells. Specifically, the role of iRhom2 on virus infection will be analyzed. During this study, the physiological role of iRhom2 will be characterized, and the involvement of other rhomboid family members on TACE maturation will be investigated. These studies will provide clarification of the differential phenotype observed between the TACE and iRhom2 deficient mice, and further define the nature of the interaction between iRhom2 and TACE. Furthermore, this research project also seeks to investigate an important potential role of iRhom2 in autoimmunity. Taken together, these specific aims will characterize the role of iRhom2 on a molecular and physiologically relevant level. The results of the proposed project will help to evaluate iRhom2 as a potential therapeutic target for TNF alpha induced disease and autoimmunity.