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Download or read book Molecular Regulation of Receptor Interacting Protein Kinase 3 Induced Cell-death in Physiology and Disease written by Kartik Gupta and published by . This book was released on 2021 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Programmed cell-death (PCD) refers to a collection of related biological pathways that dismantle cells using an underlying genetic program. Necroptosis is a form of PCD regulated by receptor interacting protein kinase (RIP/RIPK) family member RIPK3 and RIPK1. Despite our knowledge on necroptosis signaling, we do not fully understand the decision-making processes that favor necroptosis over other forms of PCD. In my thesis, I describe how the dynamic regulation of RIPK3 is linked to its role in cell-death decision making and also its extracellular role.I first report that cells respond to impending necroptosis by expelling RIPK3 in extra-cellular vesicles (EVs) including exosomes. Curiously, these EVs were also associated with increased lysosomal cargo proteins and greater numbers. This led us to postulate and identify a role of RIPK3 in MLKL dependent endosomal to lysosomal switch of EV biogenesis as a result of calcium influx. I then report the identification of a phosphorylation that is directly linked to RIPK3 protein stability during G2/M phases of the cell cycle. RIPK3 is constantly degraded by the ripoptosome which is physiologically assembled in mitosis. We discovered that S369 phosphorylation on RIPK3 by Polo-like kinase 1 during mitosis antagonizes access of ripoptosome (a complex that cleaves RIPK3), enabling this association in mitosis and elevated RIPK3 levels. Together, this solves a long-standing puzzle in the field on how RIPK3 can co-exist with the ripoptosome. RIPK3 levels are also elevated in abdominal aortic aneurysms (AAA)-a vascular disease in which the aorta undergoes pathological expansion due to the loss of vascular smooth muscle cells (SMCs) through necroptosis. Based on these data and previous work from lab members, I hypothesized that PKCÎþ mediated STAT activation causes increased Ripk3 expression via an enhancer element. Ongoing studies demonstrate that upon attenuation of this element, AAA can be rescued. In conclusion, with the help of my colleagues, I demonstrate three ways in which cellular levels of RIPK3 are regulated in physiological processes such as cell-cycle and also in diseases such as AAA. The fundamental understanding of RIPK3 biology opens avenues for therapeutic targeting of this unique cell-death factor.