Post-translational control of inflammatory cell death by XIAP

• Applicant: Dr. Monica Yabal
• Subject Area: Cell Biology ; Gastroenterology ; Immunology
• Term: from 2018 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 405101514

The regulation of cell death is immensely important for normal tissue development, proper immune responses and blocking cancer development. Increasing evidence suggests that a novel form of regulated cell death, known as necroptosis, induces strong inflammatory responses. This occurs due to the controlled release of cellular content and inflammatory cytokines. Necroptosis is now associated with severe human pathology such as sepsis, inflammatory bowel disease and cancers. However, the molecular mechanisms controlling necroptosis remain only partially understood. X-linked inhibitor of apoptosis protein (XIAP) is a critical regulator of this form of inflammatory cell death specifically within innate immune myeloid cells. These cells are key regulators of systemic immune responses. This is exemplified by the human primary immune-deficiency X-linked lymphoproliferative syndrome type 2 (XLP-2) which is caused by mutations in XIAP. Furthermore, mutations of XIAP also increase the risk of inflammatory bowel disease (IBD) in humans.So far, we know that XIAP prevents innate immune cells from dying by blocking the activation of the kinase RIPK3 (receptor-interacting serine/threonine-protein-kinase-3). Without XIAP, RIPK3 becomes spontaneously active due to Tumour necrosis factor receptor-1 and -2 (TNFR1/2) signalling. The precise mechanism behind how XIAP prevents RIPK3 activation is still unclear. Therefore, this proposal aims to examine how XIAP functions to control RIPK3 activity in the context of TNFR1/2 signalling. We will focus on the post-translation control of these signalling pathways by XIAP in innate immune cells. In addition to this molecular work, we will examine how TNFR1/2 and RIPK3 contribute to the spontaneous intestinal inflammation we have observed in our XIAP-deficient mice. The outcome of this proposal will expand our understanding of the molecular mechanisms of XIAP which control RIPK3 activation in myeloid cells. The precise characterization of this pathway has direct implications for our understanding of innate immune regulation and intestinal tissue homeostasis.

• DFG Programme: Research Grants