- Uppala, Ranjitha;
- Sarkar, Mrinal;
- Young, Kelly;
- Ma, Feiyang;
- Vemulapalli, Pritika;
- Wasikowski, Rachael;
- Plazyo, Olesya;
- Swindell, William;
- Maverakis, Emanual;
- Gharaee-Kermani, Mehrnaz;
- Billi, Allison;
- Tsoi, Lam;
- Kahlenberg, J;
- Gudjonsson, Johann
Interferon (IFN) activity exhibits a gender bias in human skin, skewed toward females. We show that HERC6, an IFN-induced E3 ubiquitin ligase, is induced in human keratinocytes through the epidermal type I IFN; IFN-κ. HERC6 knockdown in human keratinocytes results in enhanced induction of interferon-stimulated genes (ISGs) upon treatment with a double-stranded (ds) DNA STING activator cGAMP but not in response to the RNA-sensing TLR3 agonist. Keratinocytes lacking HERC6 exhibit sustained STING-TBK1 signaling following cGAMP stimulation through modulation of LATS2 and TBK1 activity, unmasking more robust ISG responses in female keratinocytes. This enhanced female-biased immune response with loss of HERC6 depends on VGLL3, a regulator of type I IFN signature. These data identify HERC6 as a previously unrecognized negative regulator of ISG expression specific to dsDNA sensing and establish it as a regulator of female-biased immune responses through modulation of STING signaling.