Najoua Lalaoui lab

The RIPK1/3 cell death molecular machinery is triggered by various innate immune ligands (e.g. TNF or TLR ligands), several therapeutics as well as under genotoxic stresses9. The formation and lethal activity of the molecular platform are tightly regulated by different molecular checkpoints including ubiquitylation, phosphorylation, cleavage or ribosylation of components of the RIPK1/3 machinery. We aim to uncover new post-translational modifications that regulate RIPK1/3 function. This project will investigate how known and unknown post-translational modifications inhibit or activate RIPK1/3-dependent cell death. Gaining a better understanding of how RIPK1/3 pro-death function is regulated will allow us to design new therapeutic approaches and anticipate mechanisms of resistance to RIPK1/3-dependent cell death.

Inappropriate activation of RIPK1/3 leads to excessive cell death and uncontrolled inflammation. In human mutations in RIPK1 or in genes encoding its regulators causes inflammatory syndromes. We will characterise new candidate mutations in RIPK1 and its regulators carried by patient affect patients affected with inflammatory disorders of unknown cause. These studies will determine the role of RIPK1/3 in development, inflammation and immune responses. Altogether, this knowledge will be used to understand how activation of RIPK1/3 impacts cancer treatment and cancer immunity.

We and others have shown that the RIPK1/3 molecular machinery can induce the secretion of myriad of cytokines and chemokines. The molecular mechanisms underlying the inflammatory functions of RIPK1/3 are still unclear. We aim to determine how RIPK1/3 activate inflammatory signalling pathways at the molecular level and uncover novel functions of this platform. This will provide molecular insights into the relationship between cell death and inflammation and increase our understanding on the impact of targeting RIPK1/3 in cancer.