Regulation of antiviral signaling: novel role for TAZ, RAE1 and their interaction

Viral infections represent a major public health problem as evidenced by the COVID-19 pandemic that killed ;7 million people and caused ;700 million illnesses. Disease prevention by vaccination is a major weapon against this often-deadly infection; however, it requires the continuous development of new vaccines, targeting new viral strains. Another, general way to fight all viral diseases is to boost the body own natural antiviral defenses. It is therefore critical to understand our cell antiviral mechanisms, to define how viruses can suppress it (via so-called avoidance tactics), and to find new ways to enhance such protective systems. Two similar cellular proteins called TAZ and YAP are important molecular switches that regulate the expression of genes involved in growth and differentiation. Recently, however, a new and direct (non-genetic) function of TAZ/YAP has emerged; they are suppressors of antiviral defense mechanisms. While this function may be crucial to terminate the defense when it is not needed anymore, it can also be exploited (hijacked) by viral proteins. Importantly, our lab has discovered that TAZ and YAP contain a region that is similar to viral proteins. Further, this region in viral proteins is critical for the suppression of antiviral defenses. With this scenario in mind, my goal is to define the molecular mechanisms whereby TAZ/YAP, similar to viruses, inhibit antiviral signaling. Using a multitude of cellular and molecular approaches, I will study how various TAZ regions affect various steps of antiviral signaling. The major advance I hope to gain by realizing this project is twofold: these studies will generate new insight into antiviral signaling and will provide us with novel strategies to boost antiviral defenses.