HERC6 regulates STING activity in a sex-biased manner through modulation of LATS2/VGLL3 Hippo signaling
Ranjitha Uppala,
Mrinal K. Sarkar,
Kelly Z. Young,
Feiyang Ma,
Pritika Vemulapalli,
Rachael Wasikowski,
Olesya Plazyo,
William R. Swindell,
Emanual Maverakis,
Mehrnaz Gharaee-Kermani,
Allison C. Billi,
Lam C. Tsoi,
J. Michelle Kahlenberg,
Johann E. Gudjonsson
Affiliations
Ranjitha Uppala
Graduate Program in Immunology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA
Mrinal K. Sarkar
Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA
Kelly Z. Young
Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA
Feiyang Ma
Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA
Pritika Vemulapalli
Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA
Rachael Wasikowski
Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA
Olesya Plazyo
Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA
William R. Swindell
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Emanual Maverakis
Department of Dermatology, University of California, Davis, Davis, CA 95616, USA
Mehrnaz Gharaee-Kermani
Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
Allison C. Billi
Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA
Lam C. Tsoi
Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA
J. Michelle Kahlenberg
Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA; A. Alfred Taubman Medical Research Institute, Ann Arbor, MI 48109, USA
Johann E. Gudjonsson
Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA; A. Alfred Taubman Medical Research Institute, Ann Arbor, MI 48109, USA; Corresponding author
Summary: 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.
