The group headed by Pierre Génin develops a project centered on the function of the protein Optineurin. Optn is an extremely versatile protein that functions in membrane trafficking pathways associated with secretion and endocytosis and in host defense against pathogens. Optn gene has been linked to diverse pathological processes such as open angle glaucoma, amyotrophic lateral sclerosis and Paget’s disease of bone. We uncovered an important function for Optn in the regulation of cell division. Interestingly, we found that this new function of Optn was dependent on its translocation from the Golgi apparatus to the nucleus upon phosphorylation by Plk1 (a kinase playing essential roles in mitotic checkpoints, mitotic exit and cytokinesis). This nuclear function of Optn relies on its ability to interact with a phosphatase complex, which, upon phosphorylation by a mitotic kinase, interacts with and inhibits Plk1. In agreement with this new mitotic function of Optn, we observed that silencing Optn induces multinucleation caused by cytokinesis and chromosome segregation defects.
The first axis of our research is to investigate the molecular mechanisms responsible for the mitotic function of Optn. The second axis of our project is to understand the function of Optn in host defense against pathogens. We are particularly interested in the molecular mechanisms by which Optn inhibits antiviral signaling and our results demonstrate that its phosphorylation by the innate immune kinase TBK1 is necessary for this regulatory function. Optn has also been shown to be involved in autophagy triggered by Salmonella enterica infection. It has been proposed that Optn regulation of the autophagy process also relied on its phosphorylation by TBK1. Thus, Optn phosphorylation by two distinct kinases, TBK1 and Plk1 governs different Optn functions and we are particularly interested to understand how the functions of Optn in host defense against pathogens are coordinated during mitosis. Together, these major projects will lead to fundamental new insights into basic cell biology processes that occur upon infection and during cell division. In addition, the role of Optn post-translational modifications that we have identified (phosphorylation and ubiquitylation) will constitute a major thrust of our research. These projects will also address the molecular basis of various human pathologies, ranging from genetic disorders to infections and may ultimately have major medical implications for the treatment of patients with these disorders.