Mild acidity likely accelerates the physiological matriptase autoactivation process: a comparative study between spontan
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RESEARCH ARTICLE
Mild acidity likely accelerates the physiological matriptase autoactivation process: a comparative study between spontaneous and acid‑induced matriptase zymogen activation Bailing Jia1,2 · Hamishi A. Thompson2 · Robert B. Barndt2 · Yi‑Lin Chiu2,3 · Mon‑Juan Lee2,4,5 · See‑Chi Lee2 · Jehng‑Kang Wang3 · Hung‑Jen Tang6 · Chen‑Yong Lin2 · Michael D. Johnson2 Received: 25 June 2020 / Accepted: 5 August 2020 © Japan Human Cell Society 2020
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. Keywords Matriptase · Zymogen activation · Acidity
Dr. Bailing Jia has conducted most of the experiments in the current study. * Hung‑Jen Tang [email protected]
3
Department of Biochemistry National Defense Medical Center, Taipei 114, Taiwan
* Chen‑Yong Lin [email protected]
4
Department of Bioscience Technology, Chang Jung Christian University, Tainan 71101, Taiwan
* Michael D. Johnson [email protected]
5
Department of Medical Science, Chang Jung Christian University, Tainan 71101, Taiwan
6
Section of Infectious Diseases, Internal Medi
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