Transcriptional regulation of RIPK3 and its impact on the sensitivity to necroptosis

• Grant number: 17/15153-8
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: November 01, 2017
• End date: October 31, 2018
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Ricardo Weinlich
• Grantee: Giulia Maria Ramella
• Host Institution: Instituto Israelita de Ensino e Pesquisa Albert Einstein (IIEPAE). Sociedade Beneficente Israelita Brasileira Albert Einstein (SBIBAE). São Paulo , SP, Brazil

Abstract

The term necroptosis designate a type of biochemically controlled necrosis-like cell death. Its first described molecular pathway occurs, in general lines, through RIPK1 (receptor-interacting serine-threonine kinase 1) that recruits RIPK3 (receptor-interacting serine-threonine kinase 3), which, in turn, recruits and phosphorylates MLKL (mixed lineage kinase domain like pseudokinase) that migrates to and destabilize the plasma membrane. Later, an alternative pathway was described as dependent on RIPK3 but independent of RIPK1 and usually activated during viral infections, which puts RIPK3 as the central molecule of the necroptotic program. In addition, expression of RIPK3 gene seems to be modulated in several pathophysiological processes, such as cancer, neurodegenerative diseases, ischemia and inflammation. Nevertheless, very little is known about RIPK3 gene modulation. Therefore, the goal of this project is to identify its promoter region and elucidate how RIPK3 regulation alters the sensitivity to the necroptotic stimuli. The potential relevance of this study is not limited only to the understanding of how a central gene of the necroptotic program is regulated, but also to point out specific targets for pharmacologic intervention in processes related to necroptosis. (AU)