Proton-activated chloride channel PACC1 as acid sensor in epidermal desquamation
Abstract
The acidic microenvironment of the stratum corneum is crucial for epidermal desquamation and barrier homeostasis, yet the primary proton sensor that triggers this process remains unknown. Here, we report that the proton-activated chloride channel PACC1 is essential for acid-induced upregulation of kallikreins (KLKs) and desmosomal degradation, two key steps in skin exfoliation. Functional and protein expression analyses revealed that PACC1 is the predominant acid-sensitive ion channel in keratinocytes. Proton-mediated PACC1 activation evokes chloride efflux and initiates a signaling cascade via the c-Jun N-terminal Kinase/AP-1 (JNK/AP-1) pathway. This cascade significantly enhances the expression and secretion of KLKs (KLK5/7), thereby facilitating desquamation through corneodesmosomal degradation. Notably, acid-induced KLK upregulation was abolished by PACC1 knockdown, knockout, or mutants that are deficient in proton sensing. This effect was also observed with pharmacological channel inhibition and was specifically restored by reconstitution with functional PACC1. These findings establish PACC1 as the core sensor that converts epidermal acidification into a desquamation signal, providing a mechanistic foundation for developing targeted therapeutic and cosmetic strategies that modulate skin barrier function.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (16)
Keyu Xia
State Key Laboratory of Virology and Biosafety, Hubei Provincial Research Center for Basic Biological Sciences, TaiKang Center for Life and Medical Sciences, College of Life Sciences, Hubei Key Laboratory of Cell Homeostasis, Frontier Science Center for Immunology and Metabolism, Department of Psychiatry, Renmin Hospital of Wuhan University, Wuhan University
Xiangjian Liu
State Key Laboratory of Virology and Biosafety, Hubei Provincial Research Center for Basic Biological Sciences, College of Life Sciences, TaiKang Center for Life and Medical Sciences, Hubei Key Laboratory of Cell Homeostasis, Frontier Science Center for Immunology and Metabolism, Wuhan University
Jiajing Wu
Junyan Hu
State Key Laboratory of Virology and Biosafety, Hubei Provincial Research Center for Basic Biological Sciences, College of Life Sciences, TaiKang Center for Life and Medical Sciences, Hubei Key Laboratory of Cell Homeostasis, Frontier Science Center for Immunology and Metabolism, Wuhan University
Xufeng Cheng
State Key Laboratory of Virology and Biosafety, Hubei Provincial Research Center for Basic Biological Sciences, College of Life Sciences, TaiKang Center for Life and Medical Sciences, Hubei Key Laboratory of Cell Homeostasis, Frontier Science Center for Immunology and Metabolism, Wuhan University
Tingyan Mi
Estée Lauder Companies Innovation R&D (China) Co. Ltd.
Bomin Gao
State Key Laboratory of Virology and Biosafety, Hubei Provincial Research Center for Basic Biological Sciences, TaiKang Center for Life and Medical Sciences, College of Life Sciences, Hubei Key Laboratory of Cell Homeostasis, Frontier Science Center for Immunology and Metabolism, Department of Psychiatry, Renmin Hospital of Wuhan University, Wuhan University
Xiaoyi Mo
Division of Spine Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University
Xuteng Lu
State Key Laboratory of Virology and Biosafety, Hubei Provincial Research Center for Basic Biological Sciences, TaiKang Center for Life and Medical Sciences, College of Life Sciences, Hubei Key Laboratory of Cell Homeostasis, Frontier Science Center for Immunology and Metabolism, Department of Psychiatry, Renmin Hospital of Wuhan University, Wuhan University
Feng Cao
Chang Xie
Department of Sports Medicine of the Second Affiliated Hospital, and Liangzhu Laboratory, Zhejiang University School of Medicine
Jian Cao
Chinese Academy of Sciences Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences
Nadine Pernodet
Global Research and Development, The Estée Lauder Companies
Guangwen He
Estée Lauder Companies Innovation R&D (China) Co. Ltd.
Huanjun Zhou
Estée Lauder Companies Innovation R&D (China) Co. Ltd.
Jing Yao