Deciphering the roles of HDAC6 in the innate immune system

ended

Macrophages are key cellular components of innate immunity. During inflammation, they respond to danger signals by inducing gene expression or altering pre-existing proteins. One such post-translational modification is carried out by histone deacetylases, enzymes that remove acetyl groups from lysine. HDAC6 is a unique member of this family due to its cytoplasmic localisation and its structure (two catalytic domains and one zinc finger ubiquitin binding domain). Several targets of HDAC6 have been identified, including, recently, the mitochondrial protein mitofusin1, which induces mitochondrial fusion upon its deacetylation. Mitochondrial dynamics control several cellular functions, including inflammatory and antimicrobial pathways. My exciting project is based on strong preliminary data; there is no doubt that HDAC6 regulates mitochondrial dynamics and contributes to antibacterial functions, however the exact mechanism and the importance of each HDAC6 domain remains unclear. Thus, I will identify the exact role of HDAC6 and its three domains on the mitochondrial dynamics and the immune response in general. This project will also contribute to the characterization of new HDAC6-dependent pathways and HDAC6 substrates involved in the inflammatory response, delivering potential targets for future research. This proposal is based on an ideal synergy between the host laboratory (expertise in HDAC6 and proteomic analysis) and me (expertise in macrophage, mitochondria and microscopy). Thus, this project is highly feasible and combines: 1) an in-depth investigation of the role of HDAC6 on mitochondrial dynamics and immune response as well as 2) an analysis of HDAC6-dependent metabolites and 3) an unbiased acetylome screen. This project is perfectly in line with the Horizon 2020 Programme objectives. It will enhance my competences through advanced training and mentorship, allowing me to reintegrate with the European research environment and establish my own research group.