Hepsin, a cell membrane-associated protease. Characterization, tissue distribution, and gene localization.

Tsuji, Akihiko; Torres-Rosado, Adrian; Arai, T; Beau, Michelle M. Le; Lemons, R S; Chou, S Y; Kurachi, Kotoku

doi:10.1016/s0021-9258(18)55395-3

Cited by 101 publications

(13 citation statements)

References 31 publications

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“…the upper respiratory tract (from nasal cavity to larynx) and the lower respiratory tract (trachea and lungs). According to the GTEx RNA-seq database [21], three TTSPs: HPN (hepsin), TMPRSS2, and ST14 (matriptase) are expressed at high levels in healthy human lungs, while TMPRSS3 and TMPRSS13 are expressed at lower levels, in agreement with several publications Figure 1B [22][23][24][25][26]. Furthermore, other reports show low expression of TMPRSS11E (DESC1) in the lungs [27] and predominant expression of TMPRSS11D (HAT, human airway trypsin) and TMPRSS11A (HATL1, human airway trypsin like 1) in the human trachea [28,29].…”

Section: Introductionsupporting

confidence: 79%

Inhibitors of type II transmembrane serine proteases in the treatment of diseases of the respiratory tract – A review of patent literature

Murza

Dion

Boudreault

et al. 2020

Expert Opinion on Therapeutic Patents

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Introduction: Type II transmembrane serine proteases (TTSPs) of the human respiratory tract generate high interest owing to their ability, among other roles, to cleave surface proteins of respiratory viruses. This step is critical in the viral invasion of coronaviruses, including SARS-CoV-2 responsible for COVID-19, but also influenza viruses and reoviruses. Accordingly, these cell surface enzymes constitute appealing therapeutic targets to develop host-based therapeutics against respiratory viral diseases. Additionally, their deregulated levels or activity has been described in non-viral diseases such as fibrosis, cancer, and osteoarthritis, making them potential targets in these indications Areas covered: Areas covered: This review includes WIPO-listed patents reporting small molecules and peptide-based inhibitors of type II transmembrane serine proteases of the respiratory tract. Expert opinion: Expert opinion: Several TTSPs of the respiratory tract represent attractive pharmacological targets in the treatment of respiratory infectious diseases (notably COVID-19 and influenza), but also against idiopathic pulmonary fibrosis and lung cancer. The current emphasis is primarily on TMPRSS2, matriptase, and hepsin, yet other TTSPs await validation. Compounds listed herein are predominantly peptidomimetic inhibitors, some with covalent reversible mechanisms of action and high potencies. Their selectivity profile, however, are often only partially characterized.Preclinical data are promising and warrant further advancement in the above diseases.

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Section: Introductionsupporting

confidence: 79%

Inhibitors of type II transmembrane serine proteases in the treatment of diseases of the respiratory tract – A review of patent literature

Murza

Dion

Boudreault

et al. 2020

Expert Opinion on Therapeutic Patents

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“…48 Hepsin 2/2 mice have reduced serum HGF. 49 Hepsin is a membrane-associated serine protease that is predominantly expressed in hepatocytes of the liver, 49,50 and its proteolytic activity is inhibited by HAI-2. 51,52 Interestingly, the extent of serum HGF reduction by excess Hai-2 is comparable to that seen in Hepsin 2/2 mice.…”

Section: Increased Expression Of the Hepatocyte Growth Factor Activator Inhibitor-2 In The Liver Does Not Alter Hepcidin Expressionmentioning

confidence: 99%

The ectodomain of matriptase-2 plays an important nonproteolytic role in suppressing hepcidin expression in mice

Enns

Jue

Zhang

2020

Blood

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Matriptase-2 (MT2), encoded by TMPRSS6, is a membrane-anchored serine protease, which plays a key role in suppressing hepatic hepcidin expression. MT2 is synthesized as a zymogen and undergoes autocleavage for activation. Previous studies suggest that MT2 suppresses hepcidin by cleaving hemojuvelin (HJV) and other components of the BMP-signaling pathway. However, the underlying mechanism is still debatable. Here we dissected the contributions of the non-proteolytic and proteolytic activities of Mt2 by taking advantage of Mt2 mutants and Tmprss6-/- mice. Studies of the protease-dead full-length Mt2 (Mt2S762A) and the truncated Mt2 that lacks the catalytic domain (Mt2mask) indicate that the catalytic domain, but not its proteolytic activity, was required for Mt2 to suppress hepcidin expression. This process was likely accomplished by the binding of Mt2 ectodomain to Hjv and Hfe. We found that Mt2 specifically cleaved the key components of the hepcidin induction pathway including Hjv, Alk3, ActRIIA, and Hfe when overexpressed in hepatoma cells. Nevertheless, studies of a murine IRIDA-causing mutant (Mt2I286F) in the CUB domain indicate that Mt2I286F can be activated but it displayed a largely compromised ability to suppress hepcidin expression. Co-immunoprecipitation analysis revealed that Mt2I286F, but not Mt2S762A, had reduced interactions with Hjv, ActRIIA, and Hfe. Additionally, increased expression of the serine protease inhibitor Hai-2 in the liver failed to alter hepcidin. Together these observations support the idea that the substrate interaction with Mt2 plays a determinant role, and suggest that the proteolytic activity is not an appropriate target to modulate the function of MT2 for clinical applications.

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“…Hepsin expression is most abundant in the liver [70], an organ where most blood coagulation factors are made. In mammalian cells and zebrafish [71,72], hepsin activates factor VII, leading to the idea that hepsin is involved in blood coagulation.…”

Section: Hepsin Functions In Individual Tissuesmentioning

confidence: 99%

Hepsin: a multifunctional transmembrane serine protease in pathobiology

Wang

Sun

et al. 2020

The FEBS Journal

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Cell membrane-bound serine proteases are important in the maintenance of physiological homeostasis. Hepsin is a type II transmembrane serine protease highly expressed in the liver. Recent studies indicate that hepsin activates prohepatocyte growth factor in the liver to enhance Met signaling, thereby regulating glucose, lipid, and protein metabolism. In addition, hepsin functions in nonhepatic tissues, including the adipose tissue, kidney, and inner ear, to regulate adipocyte differentiation, urinary protein processing, and auditory function, respectively. In mouse models, hepsin deficiency lowers blood glucose, lipid, and protein levels, impairs uromodulin assembly in renal epithelial cells, and causes hearing loss. Elevated hepsin expression has also been found in many cancers. As a type II transmembrane protease, cell surface expression and zymogen activation are essential for hepsin activity. In this review, we discuss the current knowledge regarding hepsin biosynthesis, activation, and functions in pathobiology.

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Hepsin, a cell membrane-associated protease. Characterization, tissue distribution, and gene localization.

Cited by 101 publications

References 31 publications

Inhibitors of type II transmembrane serine proteases in the treatment of diseases of the respiratory tract – A review of patent literature

Inhibitors of type II transmembrane serine proteases in the treatment of diseases of the respiratory tract – A review of patent literature

The ectodomain of matriptase-2 plays an important nonproteolytic role in suppressing hepcidin expression in mice

Hepsin: a multifunctional transmembrane serine protease in pathobiology

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