The Developmental Transcription Factor P63 Is Redeployed to Drive Allergic Skin Inflammation Through Phosphorylation by P38α

Overview

Journal J Immunol

Specialty Allergy & Immunology

Date 2022 May 27

PMID 35623662

Authors

Yanek Jimenez-Andrade

Kathryn R Hillette

Toshimi Yoshida

Mariko Kashiwagi

Min-Kyung Choo

Yinming Liang

Katia Georgopoulos

Jin Mo Park

Affiliations

Soon will be listed here.

Abstract

Keratinocytes, the epithelial cells of the skin, reprogram their gene expression and produce immune effector molecules when exposed to environmental and endogenous triggers of inflammation. It remains unclear how keratinocytes process physiological signals generated during skin irritation and switch from a homeostatic to an inflammatory state. In this article, we show that the stress-activated protein kinase p38α is crucial for keratinocytes to prompt changes in their transcriptome upon cytokine stimulation and drive inflammation in allergen-exposed skin. p38α serves this function by phosphorylating p63, a transcription factor essential for the lineage identity and stemness of the skin epithelium. Phosphorylation by p38α alters the activity of p63 and redeploys this developmental transcription factor to a gene expression program linked to inflammation. Genetic ablation and pharmacological inhibition of p38α or the p38α-p63 target gene product MMP13 attenuate atopic dermatitis-like disease in mice. Our study reveals an epithelial molecular pathway promoting skin inflammation and actionable through treatment with topical small-molecule therapeutics.

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