Genetic dissection of the mechanisms coordinating immunity and metabolism

• Applicant: Professorin Dr. Mirka Uhlirova
• Subject Area: General Genetics and Functional Genome Biology ; Developmental Biology
• Term: from 2018 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 404101084

Integration of immune and metabolic functions is fundamental for normal development and healthy lifespan. While the immune system responds to stress and fights off pathogens, the metabolic system orchestrates a balance between energy storage and expenditure. As immune activation is energetically costly, precise coordination is needed to mount an effective defense while sustaining other vital processes. The metabolic and immune functions are controlled by shared or overlapping evolutionarily conserved signaling pathways, disruption of which underlies several human diseases including diabetes, metabolic syndrome, chronic inflammatory disorders and cancer. Deciphering the factors that link metabolism and immunity is, therefore, of major interest. The stress inducible Activating transcription factor 3 (Atf3) has emerged as a potent negative regulator of NF-κB-mediated immune responses and changes to Atf3 expression have been observed in patients suffering from obesity, Crohn’s disease or cancer. Our work using the Drosophila model showed that Atf3 expression is tightly regulated during fly development and manipulating its levels in either direction has detrimental consequences. We established Atf3 as a safeguard of immune and metabolic homeostasis. We showed that loss of atf3 resulted in lipid overload and runaway inflammation, causing energy imbalance and premature death. We further demonstrated that Atf3 expression rises in response to a breakdown of epithelial integrity and its ectopic activity interferes with epithelial morphogenesis, stemming from disturbed cytoskeleton dynamics, cell adhesion and intracellular trafficking . The association of deregulated Atf3 activity with immune and metabolic imbalance, altered cytoarchitecture and human diseases calls for a better understanding of Atf3 function in both normal and pathological settings. Building on our published and preliminary data, utilizing Drosophila model, this proposal aims (1) to identify and characterize the adipose tissue-specific genetic program controlled by Atf3 that is key to immune and metabolic homeostasis, (2) to define mechanisms that drive immune cell interactions with the adipose tissue, (3) to determine how impairing microtubule cytoskeleton and cellular trafficking contribute to the immune-metabolic phenotypes caused by Atf3 malfunction, and (4) to determine the role of Atf3 in immune cells. Our work will provide novel insights into mechanisms by which transcription factors control immune and metabolic homeostasis, orchestrate immune cell functions and coordinate inter-organ communication. We hope to identify effectors that can be exploited in the context of regulating tissue physiology and inflammatory-metabolic diseases. We believe our proposed project will be of general importance for basic as well as biomedical research.

• DFG Programme: Research Grants