Depletion of Gsdma1/2/3 alleviates PMA-induced epidermal hyperplasia by inhibiting the EGFR-Stat3/Akt pathway

Qiyao Liu; Manyun Li; Minli Sun; Ruyue Xin; Yushu Wang; Qin Chen; Xiang Gao; Zhaoyu Lin

doi:10.1093/jmcb/mjad080

Depletion of Gsdma1/2/3 alleviates PMA-induced epidermal hyperplasia by inhibiting the EGFR-Stat3/Akt pathway

J Mol Cell Biol. 2023 Dec 19:mjad080. doi: 10.1093/jmcb/mjad080. Online ahead of print.

Authors

Qiyao Liu¹, Manyun Li¹, Minli Sun¹, Ruyue Xin¹, Yushu Wang¹, Qin Chen², Xiang Gao¹, Zhaoyu Lin¹

Affiliations

¹ MOE Key Laboratory of Model Animals for Disease Study, State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center, National Resource Center for Mutant Mice of China, Nanjing Drum Tower Hospital, School of Medicine, Nanjing University, Nanjing 210061, China.
² Department of Oral Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200240, China.

PMID: 38115633
DOI: 10.1093/jmcb/mjad080

Abstract

Homeostasis of the skin barrier is essential for maintaining normal skin function. Gasdermin A (GSDMA) is highly expressed in the skin and is associated with many skin diseases, such as melanoma and psoriasis. In mice, GSDMA is encoded by three gene homologues, namely Gsdma1, Gsdma2, and Gsdma3. Although Gsdma3 gain-of-function mutations cause hair loss and skin inflammation, Gsdma3-deficient mice show no phenotypes in skin or hair structures. To explore the physiological function of GSDMA, we generated conventional Gsdma1/2/3 knockout (KO) mice. We found that Gsdma1/2/3 KO mice showed significantly decreased epidermal hyperplasia and inflammation induced by phorbol 12-myristate 13-acetate (PMA). Furthermore, we found that the alleviation of epidermal hyperplasia depends on Gsdma1/2/3 expressed specifically in keratinocytes. Mechanistically, Gsdma1/2/3 depletion downregulated epidermal growth factor receptor (EGFR) ligands, leading to decreased EGFR-Stat3/Akt signalling. These results demonstrate that depletion of Gsdma1/2/3 alleviates PMA-induced epidermal hyperplasia partially by inhibiting the EGFR-Stat3/Akt pathway.

Keywords: Akt; EGFR; GSDMA; Hb-egf; PMA; Stat3; epidermal hyperplasia.