TY - JOUR
T1 - HERC6 regulates STING activity in a sex-biased manner through modulation of LATS2/VGLL3 Hippo signaling
AU - Uppala, Ranjitha
AU - Sarkar, Mrinal K.
AU - Young, Kelly Z.
AU - Ma, Feiyang
AU - Vemulapalli, Pritika
AU - Wasikowski, Rachael
AU - Plazyo, Olesya
AU - Swindell, William R.
AU - Maverakis, Emanual
AU - Gharaee-Kermani, Mehrnaz
AU - Billi, Allison C.
AU - Tsoi, Lam C.
AU - Kahlenberg, J. Michelle
AU - Gudjonsson, Johann E.
N1 - Publisher Copyright:
© 2024 The Author(s)
PY - 2024/2/16
Y1 - 2024/2/16
N2 - 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.
AB - 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.
KW - Bioinformatics
KW - Cell biology
KW - Molecular biology
KW - Omics
UR - http://www.scopus.com/inward/record.url?scp=85184056910&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85184056910&partnerID=8YFLogxK
U2 - 10.1016/j.isci.2024.108986
DO - 10.1016/j.isci.2024.108986
M3 - Article
C2 - 38327798
AN - SCOPUS:85184056910
SN - 2589-0042
VL - 27
JO - iScience
JF - iScience
IS - 2
M1 - 108986
ER -