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

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

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

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.

Published in iScience

ISSN: 2589-0042 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science
Website: http://www.cell.com/iscience/home

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