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Matriptase and prostasin proteolytic activities are differentially regulated in normal and wounded skin

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Abstract

Orchestrated control of multiple overlapping and sequential processes is required for the maintenance of epidermal homeostasis and the response to and recovery from a variety of skin insults. Previous studies indicate that membrane-associated serine protease matriptase and prostasin play essential roles in epidermal development, differentiation, and barrier formation. The control of proteolysis is a highly regulated process, which depends not only on gene expression but also on zymogen activation and the balance between protease and protease inhibitor. Subcellular localization can affect the accessibility of protease inhibitors to proteases and, thus, also represents an integral component of the control of proteolysis. To understand how membrane-associated proteolysis is regulated in human skin, these key aspects of matriptase and prostasin were determined in normal and injured human skin by immunohistochemistry. This staining shows that matriptase is expressed predominantly in the zymogen form at the periphery of basal and spinous keratinocytes, and prostasin appears to be constitutively activated at high levels in polarized organelle-like structures of the granular keratinocytes in the adjacent quiescent skin. The membrane-associated proteolysis appears to be elevated via an increase in matriptase zymogen activation and prostasin protein expression in areas of skin recovering from epidermal insults. There was no noticeable change observed in other regulatory aspects, including the expression and tissue distribution of their cognate inhibitors HAI-1 and HAI-2. This study reveals that the membrane-associated proteolysis may be a critical epidermal mechanism involved in responding to, and recovering from, damage to human skin.

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Acknowledgements

This study was supported by National Cancer Institute (NCI) Grant RO1 CA 123223 (to MDJ and CYL), Grant (MAB-108-079) from the Ministry of National Defense Medical Affairs Bureau, Taiwan, Grants (CMNDMC10705; CMNDMC10813) from Chi-Mei Medical Center, Tainan, Taiwan (to J.-K. Wang). Grants (TMU105-AE1-B02, N201711050, N201802043, and TMU IIT-107-009) from Shuang-Ho Hospital, Taipei Medical University (to S.-C. Chang), Grant (10801-62-068) from the Department of Health, Taipei City Government, and Grant (TPCH-1080-11) from Taipei City Hospital, Taiwan (to C.-H. Lai). The authors also acknowledge the assistance provided by the Microscopy and Imaging Shared Resource and the Tissue Culture Shared Resource, which are supported in part by the Lombardi Comprehensive Cancer Center support grant (NIH/NCI grant P30-CA051008). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Authors and Affiliations

  1. Division of Plastic Surgery, Integrated Burn and Wound Care Center, Department of Surgery, Shuang-Ho Hospital, New Taipei City, 235, Taiwan

    Shun-Cheng Chang

  2. Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan

    Shun-Cheng Chang

  3. Department of Dermatology, Tri-Service General Hospital, Taipei, 114, Taiwan

    Chien-Ping Chiang

  4. Department of Biochemistry, National Defense Medical Center, No. 161, Sec. 6, Ming-Chung E. Rd, Taipei, 114, Taiwan

    Chien-Ping Chiang, Yu-Sin Hung, Yu-Hsuan Chen, Hui-Yu Yang, Hao-Yu Fang & Jehng-Kang Wang

  5. Department of Dentistry Renai Branch, Taipei City Hospital, Taipei, 106, Taiwan

    Chih-Hsin Lai

  6. Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University, W412 Research Building, 3970 Reservoir Road NW, Washington, DC, 20057, USA

    Po-Wen A. Du, Michael D. Johnson & Chen-Yong Lin

  7. Department of Biomedical Engineering, National Defense Medical Center, Taipei, 114, Taiwan

    Shiao-Pieng Lee

  8. Department of Oral and Maxillofacial Surgery, Tri-Service General Hospital, Taipei, 114, Taiwan

    Shiao-Pieng Lee

  9. Section of Infectious Diseases, Internal Medicine, Chi-Mei Medical Center, No.901, Chung-Hwa Rd., Yung-Kang Dist., Tainan City, 71004, Taiwan, ROC

    Hung-Jen Tang

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  1. Shun-Cheng Chang
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  13. Chen-Yong Lin
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Corresponding authors

Correspondence to Hung-Jen Tang, Jehng-Kang Wang or Chen-Yong Lin.

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Conflict of interest

CYL is an inventor on US patents #6,077,938 (Title: Monoclonal antibody to an 80-kDa protease) and #6,677,377 (Title: Structure based discovery of inhibitors of matriptase for the cancer diagnosis and therapy by detection and inhibition of matriptase activity) and MDJ and CYL are inventors on US patent #7,355,015 (Title: Matriptase, a serine protease and its applications).

Statement on the research involving humans

Skin specimens were obtained from patients, with written informed consent by the Shuang-Ho Hospital (SHH), Taipei Medical University (TMU) under Institutional Review Board (IRB) protocol (TMU-JIRB Forms 076/20140202; 076/20160306; 071/20160306), approved by the SHH-TMU.

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Chang, SC., Chiang, CP., Lai, CH. et al. Matriptase and prostasin proteolytic activities are differentially regulated in normal and wounded skin. Human Cell 33, 990–1005 (2020). https://doi.org/10.1007/s13577-020-00385-z

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