Uncover the role of cGAS-STING activation in megakaryocytes and platelets

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The long-term objectives of my research program are to understand how cells sense endogenous cytoplasmic DNA in different cell population, including polyploid cells, and how this impact their microenvironment and lifespan. cGAS is a cytosolic receptor that recognises microbial DNA and, importantly for this application, self-DNA released into the cytoplasm upon DNA damage. Following DNA detection, cGAS activates the type-I Interferon (IFN-I) response, which usually shapes the anti-viral response but also contribute to numerous other functions in immunity. Mechanistically, this occurs through the production of a cyclic dinucleotide, named cGAMP, by cGAS and its subsequent binding to STING adaptor protein. STING activation is responsible to engage the production of IFN-I and other pro-inflammatory molecules. Growing body of evidence demonstrated the critical role of this pathway to alert the immune system of the loss of genome integrity observed during specific context such as cell senescence, cell transformation or upon DNA repair deficiency. In contrast to other immune receptors, the expression of cGAS and STING is rather ubiquitous. Nonetheless, striking differences in the outcome of cGAS-STING activation were reported for distinct cell populations ranging from cross-presentation, induction of apoptosis, and stimulation of autophagy. Such differences underline the importance to study the pathway in specific cell populations including in polyploid cells such as megakaryocytes. MKs have a critical role in haemostasis by supporting the fluctuating demand in platelets and by shaping the bone marrow microenvironment. During their differentiation, MKs undergo endomitosis, a process of abortive mitosis in which the DNA content of MKs is expected to rise to around 32 N. MKs express innate immune receptors and produce cytokines. We have recently discovered that MKs express the proteins of the cGAS-STING pathway. Importantly, cGAS drives a basal IFN-I response that can be significantly reduced by genetic depletion of cGAS or by pharmacological inhibition of STING. Based on these findings, our objectives are to investigate the contribution of cGAS-STING signalling to the biology of megakaryocytes and to discover how this impact their environment including the function of platelets. In this application, we hypothesise that cGAS activation in MKs impact many aspects of their biology, including cytokines production, cell communication and cell viability. This hypothesis will be tested with the following short-term objectives. 1. Decipher the molecular events leading to cGAS-STING activation; 2 Define the broad outcome of cGAS-STING stimulation in MKs; 3.Determine the role of cGAS in lung megakaryocytes. This research program is expected to generate important insight into the biology of MKs and will pave the way to new area of research in fundamental biology, infectious diseases and biotechnology.