Li Siyuan, Wu Yingda, Bu Dingfang, Hu Linghan, Liu Yihe, Liu Juan, Xiang Ruiyu, Bu Wenbo, Mo Ran, Song Zhongya, Chen Zhiming, Li Dongqing, Zhang Xue, Gu Heng, Yang Yong
Genetic Skin Disease Center, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Hospital for skin diseases, Institute of Dermatology, Chinese Academy of Medical Sciences & Peking Union Medical College, Nanjing, China.
Department of Dermatology, Peking University First Hospital, Beijing Key Laboratory of Molecular Diagnosis on Dermatoses, National Clinical Research Center for Skin and Immune Diseases, Beijing, China.
J Invest Dermatol. 2025 Feb;145(2):359-369.e8. doi: 10.1016/j.jid.2024.05.025. Epub 2024 Jun 22.
Nagashima-type palmoplantar keratoderma is an autosomal recessive genodermatosis caused by loss-of-function variants in SERPINB7 and is the most prevalent form of inherited palmoplantar keratodermas among Asians. However, there is currently no effective therapy for Nagashima-type palmoplantar keratoderma because its pathogenesis remains unclear. In this study, Serpinb7 mice were generated and spontaneously developed a disrupted skin barrier, which was further exacerbated by acetone-ether-water treatment. The skin of these Serpinb7 mice showed weakened cytoskeletal proteins. In addition, SERPINB7 deficiency consistently led to decreased epidermal differentiation in a 3-dimensional human epidermal model. We also demonstrated that SERPINB7 was an inhibitory serpin that mainly inhibited the protease legumain. SERPINB7 bound directly with legumain and inhibited legumain activity both in vitro and in vivo. Furthermore, we found that SERPINB7 inhibited legumain in a protease-substrate manner and identified the cleavage sites of SERPINB7 as Asn and Asn. Overall, we found that SERPINB7 showed the nature of a cysteine protease inhibitor and identified legumain as a key target protease of SERPINB7. Loss of SERPINB7 function led to overactivation of legumain, which might disrupt cytoskeletal proteins, contributing to the impaired skin barrier in Nagashima-type palmoplantar keratoderma. These findings may lead to the development of therapeutic strategies for Nagashima-type palmoplantar keratoderma.
