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Mild acidity likely accelerates the physiological matriptase autoactivation process: a comparative study between spontaneous and acid-induced matriptase zymogen activation

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Abstract

The pathophysiological functions of matriptase, a type 2 transmembrane serine protease, rely primarily on its enzymatic activity, which is under tight control through multiple mechanisms. Among those regulatory mechanisms, the control of zymogen activation is arguably the most important. Matriptase zymogen activation not only generates the mature active enzyme but also initiates suppressive mechanisms, such as rapid inhibition by HAI-1, and matriptase shedding. These tightly coupled events allow the potent matriptase tryptic activity to fulfill its biological functions at the same time as limiting undesired hazards. Matriptase is converted to the active enzyme via a process of autoactivation, in which the activational cleavage is thought to rely on the interactions of matriptase zymogen molecules and other as yet identified proteins. Matriptase autoactivation can occur spontaneously and is rapidly followed by the formation and then shedding of matriptase-HAI-1 complexes, resulting in the presence of relatively low levels of the complex on cells. Activation can also be induced by several non-protease factors, such as the exposure of cells to a mildly acidic buffer, which rapidly causes high-level matriptase zymogen activation in almost all cell lines tested. In the current study, the structural requirements for this acid-induced zymogen activation are compared with those required for spontaneous activation through a systematic analysis of the impact of 18 different mutations in various structural domains and motifs on matriptase zymogen activation. Our study reveals that both acid-induced matriptase activation and spontaneous activation depend on the maintenance of the structural integrity of the serine protease domain, non-catalytic domains, and posttranslational modifications. The common requirements of both modes of activation suggest that acid-induced matriptase activation may function as a physiological mechanism to induce pericellular proteolysis by accelerating matriptase autoactivation.

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Acknowledgements

This study was supported by National Cancer Institute (NCI) Grant RO1 CA 123223 (to MDJ and CYL), and Grant (MAB-108-079) from the Ministry of National Defense Medical Affairs Bureau, Taiwan and Grants (CMNDMC10705; CMNDMC10813) from Chi-Mei Medical Center, Tainan, Taiwan (to J.-K. Wang). We 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. Department of Gastroenterology, Henan Provincial People’s Hospital, Zhengzhou, 450003, China

    Bailing Jia

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

    Bailing Jia, Hamishi A. Thompson, Robert B. Barndt, Yi-Lin Chiu, Mon-Juan Lee, See-Chi Lee, Chen-Yong Lin & Michael D. Johnson

  3. Department of Biochemistry National Defense Medical Center, Taipei, 114, Taiwan

    Yi-Lin Chiu & Jehng-Kang Wang

  4. Department of Bioscience Technology, Chang Jung Christian University, Tainan, 71101, Taiwan

    Mon-Juan Lee

  5. Department of Medical Science, Chang Jung Christian University, Tainan, 71101, Taiwan

    Mon-Juan Lee

  6. 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. Bailing Jia
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Correspondence to Hung-Jen Tang, Chen-Yong Lin or Michael D. Johnson.

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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). This does not alter our adherence to PLOS ONE policies on sharing data and materials.fficial views of the National Cancer Institute or the National Institutes of Health.

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Dr. Bailing Jia has conducted most of the experiments in the current study.

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Jia, B., Thompson, H.A., Barndt, R.B. et al. Mild acidity likely accelerates the physiological matriptase autoactivation process: a comparative study between spontaneous and acid-induced matriptase zymogen activation. Human Cell 33, 1068–1080 (2020). https://doi.org/10.1007/s13577-020-00410-1

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