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Peer-reviewedCC BY 4.0PNAS Nexus

Keratinocyte TMEM79 protects early life epidermal homeostasis and restrains STING-dependent skin inflammation

  • Mengxu Ge1
  • Danilo Predes1
  • Andrew Kwong2,3
  • Eunice To1
  • Maorong Chen1,4
  • Aakanksha Jain1
  • Wenyi Wei5
  • Jose Ordovas-Montanes2,6,7,8,9
  • Manuel Leyva-Castillo10
  • Isaac M Chiu11,12
  • Xi He1
12 affiliations
  1. 1F. M. Kirby Neurobiology Center, Boston Children’s Hospital, Harvard Medical School , Boston, MA ,
  2. 2Division of Gastroenterology, Hepatology, and Nutrition, Boston Children’s Hospital , Boston, MA ,
  3. 3Harvard Graduate Program in Biological and Biomedical Sciences, Harvard Medical School , Boston, MA ,
  4. 4Yunnan Key Laboratory of Cell Metabolism and Diseases, Center for Life Sciences, School of Life Sciences, Yunnan University ,
  5. 5Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School , Boston, MA ,
  6. 6Program in Immunology, Harvard Medical School , Boston, MA ,
  7. 7Broad Institute of MIT and Harvard , Cambridge, MA ,
  8. 8Harvard Stem Cell Institute , Cambridge, MA ,
  9. 9Ragon Institute of MGH, MIT and Harvard , Cambridge, MA ,
  10. 10Division of Immunology, Boston Children’s Hospital, Harvard Medical School , Boston, MA ,
  11. 11Department of Immunology, Harvard Medical School , Boston, MA ,
  12. 12Gene Lay Institute of Immunology and Inflammation of Brigham and Women’s Hospital, MGH, and Harvard Medical School , Boston, MA ,
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Abstract

Chronic inflammatory skin diseases are characterized by epithelial barrier dysfunction and immune dysregulation, yet the epithelial-intrinsic mechanisms that initiate inflammation remain poorly understood. TMEM79 is a dermatitis-associated transmembrane protein expressed in keratinocytes, but how its loss promotes skin disease remains unclear. Here, using keratinocyte-specific Tmem79 conditional knockout (cKO) mice and TMEM79-deficient human keratinocytes, we find that TMEM79 is required for proper epithelial differentiation and barrier formation, and that its loss induces keratinocyte stress and ferroptosis-associated lipid peroxidation. Longitudinal analysis of neonatal and early postnatal Tmem79-deficient skin revealed disrupted epidermal homeostasis and early type I IFN signaling preceding the later emergence of type 17 inflammation. Mechanistically, genetic ablation of Sting1, but not Mavs, ameliorated dermatitis and downstream type 17 inflammation, while IL-17A was required for subsequent epidermal hyperplasia. These findings establish STING-dependent signaling as an upstream driver of skin immune activation and pathology. Together, our findings link early-life epithelial stress to innate immune activation and suggest that targeting lipid peroxidation or STING signaling may help prevent inflammatory skin disease progression.

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Cite

BibTeXRIS
BibTeX
@article{ge2026keratinocyte,
  title = {{Keratinocyte TMEM79 protects early life epidermal homeostasis and restrains STING-dependent skin inflammation}},
  author = {Mengxu Ge and Danilo Predes and Andrew Kwong and Eunice To and Maorong Chen and Aakanksha Jain and Wenyi Wei and Jose Ordovas-Montanes and Manuel Leyva-Castillo and Isaac M Chiu and Xi He},
  journal = {PNAS Nexus},
  year = {2026},
  month = oct,
  doi = {10.1093/pnasnexus/pgag361},
  url = {https://academic.oup.com/pnasnexus/advance-article/doi/10.1093/pnasnexus/pgag361/9003321},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Keratinocyte TMEM79 protects early life epidermal homeostasis and restrains STING-dependent skin inflammation
AU  - Mengxu Ge
AU  - Danilo Predes
AU  - Andrew Kwong
AU  - Eunice To
AU  - Maorong Chen
AU  - Aakanksha Jain
AU  - Wenyi Wei
AU  - Jose Ordovas-Montanes
AU  - Manuel Leyva-Castillo
AU  - Isaac M Chiu
AU  - Xi He
PY  - 2026
DA  - 2026/10/28
JO  - PNAS Nexus
DO  - 10.1093/pnasnexus/pgag361
UR  - https://academic.oup.com/pnasnexus/advance-article/doi/10.1093/pnasnexus/pgag361/9003321
AB  - Chronic inflammatory skin diseases are characterized by epithelial barrier dysfunction and immune dysregulation, yet the epithelial-intrinsic mechanisms that initiate inflammation remain poorly understood. TMEM79 is a dermatitis-associated transmembrane protein expressed in keratinocytes, but how its loss promotes skin disease remains unclear. Here, using keratinocyte-specific Tmem79 conditional knockout (cKO) mice and TMEM79-deficient human keratinocytes, we find that TMEM79 is required for proper epithelial differentiation and barrier formation, and that its loss induces keratinocyte stress and ferroptosis-associated lipid peroxidation. Longitudinal analysis of neonatal and early postnatal Tmem79-deficient skin revealed disrupted epidermal homeostasis and early type I IFN signaling preceding the later emergence of type 17 inflammation. Mechanistically, genetic ablation of Sting1, but not Mavs, ameliorated dermatitis and downstream type 17 inflammation, while IL-17A was required for subsequent epidermal hyperplasia. These findings establish STING-dependent signaling as an upstream driver of skin immune activation and pathology. Together, our findings link early-life epithelial stress to innate immune activation and suggest that targeting lipid peroxidation or STING signaling may help prevent inflammatory skin disease progression.
SN  - 2752-6542
ER  -