PROJECT SUMMARY/ABSTRACT The non-lesional and lesional skin of systemic lupus erythematosus (SLE) patients is rich in type I interferons (IFNs) which contribute to a propensity for inflammation, apoptosis, and photosensitivity. Importantly, while new drugs are now approved for global blockade of type I IFN signaling in SLE, their effects may be moderate and side effects, including risk of viral infections, remain a barrier to treatment. Further, while interferons are important, there is a critical knowledge gap as to what regulates the propensity for interferon production and inflammation in SLE skin. Addressing this gap will lead to mechanistic understanding of CLE lesions that can be targeted to precisely eliminate the pathogenic players without side effects, such as those generated by global IFN blockade, and potentially prevent disease. Our novel preliminary data has uncovered a role for functional dysregulation of the Hippo signaling pathway in SLE keratinocytes through overexpression of the apical key regulator, WW domain containing protein 1 (WWC1), resulting in chronic overactivation of Hippo signaling and increased phosphorylation of Yes-associated protein (YAP). Our data also show that this skewing of YAP phosphorylation may be critical for the aberrant apoptotic responses that have been identified in SLE keratinocytes. While this data is impactful on its own, recent reports in the cancer literature also suggest that members of the Hippo pathway may be critical regulators of type I IFN production through interactions with the cGAS/STING pathway5,6. Indeed, our preliminary data identify SLE-overproduction of IFN-κ as STING- dependent and blockade of YAP phosphorylation through LATS1/2 inhibition as sufficient to block IFNK transcription after STING activation. These data form the basis of our overall hypothesis that dysregulation of Hippo signaling is a critical driver of lupus keratinocyte dysfunction and that modulation of key Hippo- signaling mediators will “normalize” lupus keratinocyte behavior. We will address this hypothesis through the following aims: Aim 1: Uncover the role of the Hippo pathway in driving enhanced SLE keratinocyte apoptosis. Aim 2: Determine the mechanisms by which Hippo signaling skews the production of type I interferons in SLE keratinocytes. Aim 3: Determine the role of Hippo signaling in UVB-mediated NF-κB- driven inflammatory responses. Successful completion of this proposal will uncover important new biology regarding the interaction of type I IFNs and Hippo signaling and identify specific Hippo pathway targets that will serve as novel targets for prevention and treatment of SLE skin disease.