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

doi:10.1016/j.isci.2024.108986

HERC6 regulates STING activity in a sex-biased manner through modulation of LATS2/VGLL3 Hippo signaling

iScience. 2024 Jan 23;27(2):108986. doi: 10.1016/j.isci.2024.108986. eCollection 2024 Feb 16.

Authors

Ranjitha Uppala^{1

2}, Mrinal K Sarkar², Kelly Z Young², Feiyang Ma², Pritika Vemulapalli², Rachael Wasikowski², Olesya Plazyo², William R Swindell³, Emanual Maverakis⁴, Mehrnaz Gharaee-Kermani^{2

5}, Allison C Billi², Lam C Tsoi², J Michelle Kahlenberg^{5

6}, Johann E Gudjonsson^{2

5

6}

Affiliations

¹ Graduate Program in Immunology, University of Michigan, Ann Arbor, MI 48109, USA.
² Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA.
³ Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
⁴ Department of Dermatology, University of California, Davis, Davis, CA 95616, USA.
⁵ Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
⁶ A. Alfred Taubman Medical Research Institute, Ann Arbor, MI 48109, USA.

Abstract

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.

Keywords: Bioinformatics; Cell biology; Molecular biology; Omics.

Abstract

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