Karolinska Research Lectures: Junying Yuan
Karolinska Research Lectures at Nobel Forum: Junying Yuan, Department of Cell Biology, Harvard Medical School, Boston, USA.
Title: “Regulation of necroptosis and inflammation by RIPK1”
Necrosis is a common pathological feature in a multitude of human diseases ranging from cancers to neurodegeneration. However, the traditional belief that necrosis was a passive form of cell death caused by overwhelming stress has stymied research in this area as well as impeded the development of therapeutic methods targeting necrosis. We demonstrated that TNFa, an important proinflammatory cytokine, could activate a regulated necrotic cell death mechanism – termed necroptosis – and developed specific small molecule inhibitors of necroptosis, the necrostatins. A chemically improved Necrostatin-1 (Nec-1) analog, R-7-Cl-O-Nec-1, turned out to be a highly specific inhibitor of the kinase activity of RIPK1. The ability of Nec-1 and its analogues to inhibit necrosis in many cultured models as well as animal models of human diseases overturned the traditional dogma of necrosis as passive cell death and led to the rapid acceptance and explosion of research on necroptosis. RIPK1 has emerged as a key upstream regulator that controls necroptosis, inflammatory signaling as well as certain specific forms of apoptosis. The ability of RIPK1 to modulate these key cellular events is tightly controlled by phosphorylation and the interaction with its downstream mediators. Targeting RIPK1 might provide an exciting novel therapeutic strategy for the treatment of both acute and chronic human diseases.