Ioannis Siokas

In the Degterev Lab, we study an inflammatory form of programmed cell death called Necroptosis. Necroptosis is commonly activated under pathological conditions such as following pathogen infection or in various pulmonary, bowel, and neurodegenerative diseases. As a result, necroptosis blockade presents as an attractive target for treatment of various human pathologies. The hallmark of necroptosis activation is characterized by activation of the serine/threonine kinase, Receptor Interacting Protein Kinase 3 (RIPK3), which leads to its oligomerization and auto-phosphorylation. Once active, RIPK3 directly phosphorylates its substrate, mixed lineage kinase domain like pseudokinase, MLKL, enabling MLKL to assemble into large oligomers that are inserted into the plasma membrane, causing cell death. Because RIPK3 kinase activation is indispensable for necroptosis activation, it presents the best target to combat necroptosis associated pathologies. However, despite RIPK3 kinase activation being necessary for necroptosis activation, the molecular mechanisms that govern its kinase activity are still poorly understood. My work focuses on understanding the molecular mechanisms that control RIPK3 kinase activation and interrogate how small molecule inhibitors of RIPK3 interfere with this process to prevent necroptosis.