Signaling and Pathogenesis laboratory head by Robert WEIL is involved in the study of three signaling pathways, NF-kappaB, Optineurin and Notch, using essentially biochemical, genetic and cell biology approaches.
Group “NF-κB signaling in response to antigen stimulation” (R. WEIL): NF-κB activation represents a general stress response, involved among others in the immune, inflammatory and anti-apoptotic responses. Its dysfunction is associated with a number of pathologies, cancer being only one of them. Members of this group are working on the activation of NF-κB in response to T cell receptor (TCR) stimulation. They have recently identified a new upstream component of this cascade and study its role in physiological and pathological situations.
Group “Physiological and pathological regulation of NF-κB signaling” (E. LAPLANTINE): The activity of the NF-κB cascade is controlled by a series of post-translational modifications, non-degradative ubiquitination being the last one to be discovered. This group is currently studying the mechanisms that control the complex network of ubiquitinated molecules and ubiquitin receptors involved in NF-κB signaling, both under normal and pathological conditions. In particular, they study the regulation of the activity of NEMO, the core element of the NF-κB signaling pathway, focusing on its ability to bind different types of polyubiquitin chains. They have identified a family of proteins, which use the same ubiquitin-binding domains as NEMO, and are characterizing new members of this family.
Group “Optineurin functions in normal and pathological conditions” (P. GENIN): Our ongoing studies of the NF-κB pathway led Robert Weil’ laboratory to identify and characterize a protein named Optineurin (Optn). Despite its homology with NEMO, numerous studies indicate that Optn is involved in apparently NF-κB unrelated functions, including membrane trafficking, secretion, antiviral innate immune response, selective autophagy of Salmonella enterica and mitotic control. In addition, mutations in the Optn gene have been associated with primary open-angle glaucoma (POAG), amyotrophic lateral sclerosis (ALS) and Paget’s disease of bone, although the molecular mechanism by which Optn mutations lead to these pathologies is unknown. Among the different functions of Optn, we are particularly interested to its regulatory role in cell division and antiviral innate immune defense.
Group “Notch signaling in mammals” (C. BROU): The Notch pathway is involved in the development and maintenance of organs and tissues. Contrary to a number of signaling pathways, Notch does not use a cascade of kinases, but relies on complex trafficking events targeting both the receptor and its ligands, and controlled by a network of ubiquitinated proteins and ubiquitin receptors. The group of C Brou specifically studies the mechanisms that control the maintenance of an active receptor at the plasma membrane, the production of active ligands, and the regulation of signal transduction after activation. They are particularly interested in the trafficking and post-translational modifications undergone by the Notch receptor and its ligands.
Signaling and Pathogenesis is part of CNRS UMR 3691.