Dual role of the endothelium in energy homeostasis and viral infections

The network of blood and lymphatic vessels permeates every organ, sustaining their function and integrating organ systems to maintain homeostasis of the organism. Endothelial cells (ECs) lining the vasculature are increasingly recognized as dynamic regulators of tissue function and organ homeostasis. In the highly vascularized adipose tissue, endothelial health is critical for proper vascularization, excess energy storage, and metabolic homeostasis. Endothelial dysfunction disrupts adipose tissue remodeling, contributing to obesity-related and cardiovascular diseases. The vasculature also represents a key interface for host-pathogen interactions. ECs are among the first to encounter circulating pathogens. Viruses can infect them directly or trigger secondary dysfunction via viral proteins or immune responses. Thus, the endothelium must continuously balance efficient nutrient transport with antiviral protection, a trade-off whose underlying mechanisms remain incompletely understood. This thesis identifies the endothelial-specific transmembrane protein MYCT1 as a regulator of both white adipose tissue (WAT) expansion and endothelial antiviral defenses through a shared mechanism. Endothelial-specific Myct1 deletion in mice resulted in reduced WAT expansion, independently of both angiogenesis and adipogenesis. Instead, MYCT1-deficient ECs hyper-activated mTORC1 signaling. Mechanistically, we found that MYCT1 interacts with the antiviral proteins IFITM2/3 and promotes their degradation. Consequently, loss of MYCT1 led to accumulation of IFITM2/3 in early endosomes, enhancing lysosomal degradation of endocytic cargo. This results in a dual effect of enhanced antiviral protection of ECs and in increased intracellular availability of nutrients that hyper-activate mTORC1 signaling in ECs. Overall, these findings suggest that ECs have evolved to use the MYCT1-IFITM2/3 interaction to balance efficient nutrient transport with antiviral protection.