897 HERC6 is an Interferon induced E3 ubiquitin ligase that negatively regulates sex-specific STING-IRF3 responses through modulation of LATS2/VGLL3 Hippo signaling

Aberrant STING and Interferon (IFN) signaling are hallmarks of SLE, a female-biased disease, where amplified type I IFN responses by keratinocytes (KCs) lead to increased Stimulated Genes (ISGs) expression. Here we show that HERC6, which encodes for an E3 ubiquitin ligase, with unknown role in the skin, is induced basal layer human SLE epidermis coinciding marked decrease number sex-biased genes. We demonstrated cGAMP, ligand, HERC6 expression KCs IFNK dependent manner. knockdown resulted enhanced induction ISGs (p<0.005) upon cGAMP treatment, but not RNA-sensing TLR3 agonist, Poly(I:C) indicating negative regulator ISG specific dsDNA. lacking similarly exhibited sustained STING-IRF3 (p=0.0039) following stimulation. Finally, found decreased LATS2 ubiquitination stimulation, accompanied protein YAP1, resulting TBK1, activates amplifies downstream STING. Notably, observed HERC6-associated activation on transcription cofactor VGLL3, has been implicated autoimmunity. These data identify as novel sex-specific IFN/STING activity skin.