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The spatiotemporal control of human matriptase action on its physiological substrates: a case against a direct role for matriptase proteolytic activity in profilaggrin processing and desquamation

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Abstract

Studies of human genetic disorders and animal models indicate that matriptase plays essential roles in proteolytic processes associated with profilaggrin processing and desquamation at late stages of epidermal differentiation. The tissue distribution profile and zymogen activation status in human skin, however, suggests that matriptase physiological function in the skin more likely lies in the proliferating and differentiating keratinocytes in the basal and spinous layers. Marked acanthosis with expanded spinous layer and lack of significant changes in intensity and expression pattern for several terminal differentiation markers in the skin of ARIH patients support matriptase’s role in earlier rather than the later stages of differentiation. In addition to the tissue distribution, differential subcellular localization further limits the ability of extracellular matriptase proteolytic activity to access the cytosolic non-membrane-bound keratohyalin granules, in which profilaggrin processing occurs. The short lifespan of active matriptase, which results from tightly controlled zymogen activation, rapid inhibition by HAI-1, and shedding from cell surface, indicates that active matriptase likely performs physiological functions via limited proteolysis on its substrates, as needed, rather than via a continuous bulk process. We, here, review these spatiotemporal controls of matriptase proteolytic activity at the biochemical, cellular, and tissue level. Based on this in-depth understanding of how matriptase activity is regulated, we argue that there is no direct involvement of matriptase proteolytic activity in profilaggrin processing and desquamation. The defects in epidermal terminal differentiation associated with matriptase deficiency are likely secondary and are due to putative disruption at earlier stages of differentiation.

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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). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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

    Chen-Yong Lin & Michael D. Johnson

  2. Department of Biochemistry National Defense Medical Center, Taipei, 11490, Taiwan

    Jehng-Kang Wang

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  1. Chen-Yong Lin
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Correspondence to Chen-Yong Lin.

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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 the journal policies on sharing data and materials and official views of the National Cancer Institute or the National Institutes of Health.

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Lin, CY., Wang, JK. & Johnson, M.D. The spatiotemporal control of human matriptase action on its physiological substrates: a case against a direct role for matriptase proteolytic activity in profilaggrin processing and desquamation. Human Cell 33, 459–469 (2020). https://doi.org/10.1007/s13577-020-00361-7

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