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Oxidative or hypoxic stress can lead to accumulation of unfolded proteins in the endoplasmic reticulum (ER), a condition termed ER-stress. ER-stress triggers the unfolded protein response (UPR) which ameliorates accumulation of unfolded proteins by increasing ER-resident chaperones, inhibiting protein translation and accelerating degradation of unfolded proteins. However, a subset of proteins considered to contribute to stress adaptation is able to escape the translational block, thus making them particularly interesting as potential therapeutic targets in severe stress conditions.Here we report that the disintegrin and metalloproteinase protein 17 (ADAM17), also known as TNFα converting enzyme (TACE), is a novel gene induced by ER-stress and severe hypoxia. Under these stress conditions, activation of the PERK/eIF2α/ATF4 and ATF6 arms of UPR enhanced ADAM17 expression and sheddase activity. Subsequently, this pathway increased the release of TNF receptor 1 (TNFR1) in vitro and in vivo.Collectively, ADAM17 is a novel UPR-regulated gene in response to severe hypoxia and ER-stress, which is actively involved in TNFR1 release. Since ER-stress and severe hypoxia have been implicated in the progression of various cardiovascular disorders, induction and activation of ADAM17 and soluble TNFR1 may contribute to the inflammatory response under these conditions thus representing interesting new therapeutic targets.