iScience (Feb 2024)

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

Journal volume & issue
Vol. 27, no. 2
p. 108986

Abstract

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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.

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