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The Role of Protease and Protease Inhibitors in Human Diseases

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 July 2024) | Viewed by 18409

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Dr. Georgios Pampalakis

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Laboratory of Pharmacology, School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
Interests: proteases; kallikreins; prostate-specific antigen; skin (patho)physiology; organophosphates; chemobrionics

Special Issue Information

Dear Colleagues,

This Special Issue in the International Journal of Molecular Sciences entitled “The Role of Protease and Protease Inhibitors in Human Diseases” will cover a selection of recent research and review articles on the role of proteases and/or their inhibitors in human pathophysiology.

Protease processes maturate or destroy specific protein substrates while their inhibitors safeguard their activities. Usually, proteases do not work alone but they are organized in complex proteolytic cascades that amplify the activities and allow for fine-tuning. There are approximately 600 proteases and 150 endogenous protease inhibitors in humans that regulate diverse physiological processes such as cellular signaling, DNA replication, cellular proliferation and differentiation, remodeling of the extracellular matrix, angiogenesis, neurogenesis, fertilization, blood coagulation, food digestion, apoptosis, inflammation, etc. Therefore, it is not surprising that the deregulation of their activities governs multiple pathological conditions including cancer, neurodegeneration, skin overdesquamation and inflammation. In addition, recent data has shown that human endogenous proteases regulate certain viral infections.

Thus, proteases are druggable targets and important diagnostic molecules. In the latter context, the development of assays to measure their activity instead of the total amount is expected to increase their diagnostic potential since it is the activity that underlies the (patho)physiological phenotype.

Suitable topics include, but are not limited to:

Proteolytic cascades in health and disease;
Degradome;
Proteases in cancer;
Proteolysis in neurodegenerative diseases;
Epidermal pathophysiology;
Viral proteases;
Molecular diagnosis;
Prostate-specific antigen;
Extracellular matrix remodeling;
Design of protease inhibitors.

Dr. Georgios Pampalakis
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

proteases
cancer
aging
neurodegeneration
skin (patho)physiology
protease inhibitors
molecular diagnosis
biomarkers
proteolytic cascades
infection

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Published Papers (7 papers)

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Research

Jump to: Review

14 pages, 1651 KiB

Open AccessArticle

Neutrophil Elastase Targets Select Proteins on Human Blood-Monocyte-Derived Macrophage Cell Surfaces

by Nadia Tasnim Ahmed, Apparao B. Kummarapurugu, Shuo Zheng, Gamze Bulut, Le Kang, Aashish Batheja, Adam Hawkridge and Judith A. Voynow

Int. J. Mol. Sci. 2024, 25(23), 13038; https://doi.org/10.3390/ijms252313038 - 4 Dec 2024

Cited by 2 | Viewed by 1186

Abstract

Neutrophil elastase (NE) has been reported to be a pro-inflammatory stimulus for macrophages. The aim of the present study was to determine the impact of NE exposure on the human macrophage proteome and evaluate its impact on pro-inflammatory signals. Human blood monocytes from healthy volunteers were differentiated to macrophages and then exposed to either 500 nM of NE or control vehicle for 2 h in triplicate. Label-free quantitative proteomics analysis identified 41 differentially expressed proteins in the NE versus control vehicle datasets. A total of 26 proteins were downregulated and of those, 21 were cell surface proteins. Importantly, four of the cell surface proteins were proteoglycans: neuropilin 1 (NRP1), syndecan 2 (SDC2), glypican 4 (GPC4), and CD99 antigen-like protein 2 (CD99L2) along with neuropilin 2 (NRP2), CD99 antigen (CD99), and endoglin (ENG) which are known interactors. Additional NE-targeted proteins related to macrophage function were also measured including CD40, CD48, SPINT1, ST14, and MSR1. Collectively, this study provides a comprehensive unbiased view of selective NE-targeted cell surface proteins in chronically inflamed lungs. Full article

(This article belongs to the Special Issue The Role of Protease and Protease Inhibitors in Human Diseases)

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15 pages, 3122 KiB

Open AccessArticle

The Furin Protease Dependence and Antiviral GBP2 Sensitivity of Murine Leukemia Virus Infection Are Determined by the Amino Acid Sequence at the Envelope Glycoprotein Cleavage Site

by Yoshinao Kubo, Manya Bakatumana Hans, Taisuke Nakamura and Hideki Hayashi

Int. J. Mol. Sci. 2024, 25(18), 9987; https://doi.org/10.3390/ijms25189987 - 16 Sep 2024

Viewed by 840

Abstract

Host restriction factor GBP2 suppresses the replication of the ecotropic Moloney murine leukemia virus (E-MLV) by inhibiting furin protease, which cleaves the viral envelope glycoprotein (Env) into surface (SU) and transmembrane (TM) subunits. We analyzed the impacts of GBP2 on the infection efficiency mediated by MLV Envs of different strains of ecotropic Moloney, polytropic Friend, amphotropic, and xenotropic MLV-related (XMRV) viruses. Interestingly, the Envs of ecotropic Moloney and polytropic Friend MLV were sensitive to the antiviral activity of GBP2, while XMRV and amphotropic Envs showed resistance. Consistent with the sensitivity to GBP2, the amino acid sequences of the sensitive Envs at the SU-TM cleavage site were similar, as were the sequences of the resistant Envs. SU-TM cleavage of the GBP2-sensitive Env protein was inhibited by furin silencing, whereas that of GBP2-resistant Env was not. The substitution of the ecotropic Moloney cleavage site sequence with that of XMRV conferred resistance to both GBP2 and furin silencing. Reciprocally, the substitution of the XMRV cleavage site sequence with that of the ecotropic sequence conferred sensitivity to GBP2 and furin silencing. According to the SU-TM cleavage site sequence, there were sensitive and resistant variants among ecotropic, polytropic, and xenotropic MLVs. This study found that the dependence of MLV Env proteins on furin cleavage and GBP2-mediated restriction is determined by the amino acid sequences at the SU-TM cleavage site. Full article

(This article belongs to the Special Issue The Role of Protease and Protease Inhibitors in Human Diseases)

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23 pages, 9270 KiB

Open AccessArticle

Downregulation of Protease Cathepsin D and Upregulation of Pathologic α-Synuclein Mediate Paucity of DNAJC6-Induced Degeneration of Dopaminergic Neurons

by Ching-Chi Chiu, Ying-Ling Chen, Yi-Hsin Weng, Shu-Yu Liu, Hon-Lun Li, Tu-Hsueh Yeh and Hung-Li Wang

Int. J. Mol. Sci. 2024, 25(12), 6711; https://doi.org/10.3390/ijms25126711 - 18 Jun 2024

Cited by 2 | Viewed by 1548

Abstract

A homozygous mutation of the DNAJC6 gene causes autosomal recessive familial type 19 of Parkinson’s disease (PARK19). To test the hypothesis that PARK19 DNAJC6 mutations induce the neurodegeneration of dopaminergic cells by reducing the protein expression of functional DNAJC6 and causing DNAJC6 paucity, an in vitro PARK19 model was constructed by using shRNA-mediated gene silencing of endogenous DANJC6 in differentiated human SH-SY5Y dopaminergic neurons. shRNA targeting DNAJC6 induced the neurodegeneration of dopaminergic cells. DNAJC6 paucity reduced the level of cytosolic clathrin heavy chain and the number of lysosomes in dopaminergic neurons. A DNAJC6 paucity-induced reduction in the lysosomal number downregulated the protein level of lysosomal protease cathepsin D and impaired macroautophagy, resulting in the upregulation of pathologic α-synuclein or phospho-α-synuclein^Ser129 in the endoplasmic reticulum (ER) and mitochondria. The expression of α-synuclein shRNA or cathepsin D blocked the DNAJC6 deficiency-evoked degeneration of dopaminergic cells. An increase in ER α-synuclein or phospho-α-synuclein^Ser129 caused by DNAJC6 paucity activated ER stress, the unfolded protein response and ER stress-triggered apoptotic signaling. The lack of DNAJC6-induced upregulation of mitochondrial α-synuclein depolarized the mitochondrial membrane potential and elevated the mitochondrial level of superoxide. The DNAJC6 paucity-evoked ER stress-related apoptotic cascade, mitochondrial malfunction and oxidative stress induced the degeneration of dopaminergic neurons via activating mitochondrial pro-apoptotic signaling. In contrast with the neuroprotective function of WT DNAJC6, the PARK19 DNAJC6 mutants (Q789X or R927G) failed to attenuate the tunicamycin- or rotenone-induced upregulation of pathologic α-synuclein and stimulation of apoptotic signaling. Our data suggest that PARK19 mutation-induced DNAJC6 paucity causes the degeneration of dopaminergic neurons via downregulating protease cathepsin D and upregulating neurotoxic α-synuclein. Our results also indicate that PARK19 mutation (Q789X or R927G) impairs the DNAJC6-mediated neuroprotective function. Full article

(This article belongs to the Special Issue The Role of Protease and Protease Inhibitors in Human Diseases)

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16 pages, 8350 KiB

Open AccessArticle

Mmp2 Deficiency Leads to Defective Parturition and High Dystocia Rates in Mice

by Rotem Kalev-Altman, Gal Becker, Tamar Levy, Svetlana Penn, Nahum Y. Shpigel, Efrat Monsonego-Ornan and Dalit Sela-Donenfeld

Int. J. Mol. Sci. 2023, 24(23), 16822; https://doi.org/10.3390/ijms242316822 - 27 Nov 2023

Cited by 3 | Viewed by 1951

Abstract

Parturition is the final and essential step for mammalian reproduction. While the uterus is quiescent during pregnancy, fundamental changes arise in the myometrial contractility, inducing fetal expulsion. Extracellular matrix (ECM) remodeling is fundamental for these events. The gelatinases subgroup of matrix metalloproteinases (MMPs), MMP2 and MMP9, participate in uterine ECM remodeling throughout pregnancy and parturition. However, their loss-of-function effect is unknown. Here, we determined the result of eliminating Mmp2 and/or Mmp9 on parturition in vivo, using single- and double-knockout (dKO) mice. The dystocia rates were measured in each genotype, and uterine tissue was collected from nulliparous synchronized females at the ages of 2, 4, 9 and 12 months. Very high percentages of dystocia (40–55%) were found in the Mmp2^−/− and dKO females, contrary to the Mmp9^−/− and wild-type females. The histological analysis of the uterus and cervix revealed that Mmp2^−/− tissues undergo marked structural alterations, including highly enlarged myometrial, endometrial and luminal cavity. Increased collagen deposition was also demonstrated, suggesting a mechanism of extensive fibrosis in the Mmp2^−/− myometrium, which may result in dystocia. Overall, this study describes a new role for MMP2 in myometrium remodeling during mammalian parturition process, highlighting a novel cause for dystocia due to a loss in MMP2 activity in the uterine tissue. Full article

(This article belongs to the Special Issue The Role of Protease and Protease Inhibitors in Human Diseases)

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15 pages, 2290 KiB

Open AccessArticle

Unveiling the Potent Fibrino(geno)lytic, Anticoagulant, and Antithrombotic Effects of Papain, a Cysteine Protease from Carica papaya Latex Using κ-Carrageenan Rat Tail Thrombosis Model

by Hye Ryeon Yang, Most Nusrat Zahan, Yewon Yoon, Kyuri Kim, Du Hyeon Hwang, Woo Hyun Kim, Il Rae Rho, Euikyung Kim and Changkeun Kang

Int. J. Mol. Sci. 2023, 24(23), 16770; https://doi.org/10.3390/ijms242316770 - 26 Nov 2023

Cited by 4 | Viewed by 2508

Abstract

While fibrinolytic enzymes and thrombolytic agents offer assistance in treating cardiovascular diseases, the existing options are associated with a range of adverse effects. In our previous research, we successfully identified ficin, a naturally occurring cysteine protease that possesses unique fibrin and fibrinogenolytic enzymes, making it suitable for both preventing and treating cardiovascular disorders linked to thrombosis. Papain is a prominent cysteine protease derived from the latex of Carica papaya. The potential role of papain in preventing fibrino(geno)lytic, anticoagulant, and antithrombotic activities has not yet been investigated. Therefore, we examined how papain influences fibrinogen and the process of blood coagulation. Papain is highly stable at pH 4–11 and 37–60 °C via azocasein assay. In addition, SDS gel separation electrophoresis, zymography, and fibrin plate assays were used to determine fibrinogen and fibrinolysis activity. Papain has a molecular weight of around 37 kDa, and is highly effective in degrading fibrin, with a molecular weight of over 75 kDa. Furthermore, papain-based hemostatic performance was confirmed in blood coagulation tests, a blood clot lysis assay, and a κ-carrageenan rat tail thrombosis model, highlighting its strong efficacy in blood coagulation. Papain shows dose-dependent blood clot lysis activity, cleaves fibrinogen chains of Aα, Bβ, and γ-bands, and significantly extends prothrombin time (PT) and activated partial thromboplastin time (aPTT). Moreover, the mean length of the infarcted regions in the tails of Sprague–Dawley rats with κ-carrageenan was shorter in rats administered 10 U/kg of papain than in streptokinase-treated rats. Thus, papain, a cysteine protease, has distinct fibrin and fibrinogenolytic properties, suggesting its potential for preventing or treating cardiovascular issues and thrombosis-related diseases. Full article

(This article belongs to the Special Issue The Role of Protease and Protease Inhibitors in Human Diseases)

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15 pages, 3721 KiB

Open AccessArticle

A Serine Protease Inhibitor, Camostat Mesilate, Suppresses Urinary Plasmin Activity and Alleviates Hypertension and Podocyte Injury in Dahl Salt-Sensitive Rats

by Yasunobu Iwata, Qinyuan Deng, Yutaka Kakizoe, Terumasa Nakagawa, Yoshikazu Miyasato, Miyuki Nakagawa, Kayo Nishiguchi, Yu Nagayoshi, Yuki Narita, Yuichiro Izumi, Takashige Kuwabara, Masataka Adachi and Masashi Mukoyama

Int. J. Mol. Sci. 2023, 24(21), 15743; https://doi.org/10.3390/ijms242115743 - 30 Oct 2023

Cited by 1 | Viewed by 1616

Abstract

In proteinuric renal diseases, the serine protease (SP) plasmin activates the epithelial sodium channel (ENaC) by cleaving its γ subunit. We previously demonstrated that a high-salt (HS) diet provoked hypertension and proteinuria in Dahl salt-sensitive (DS) rats, accompanied by γENaC activation, which were attenuated by camostat mesilate (CM), an SP inhibitor. However, the effects of CM on plasmin activity in DS rats remain unclear. In this study, we investigated the effects of CM on plasmin activity, ENaC activation, and podocyte injury in DS rats. The DS rats were divided into the control diet, HS diet (8.0% NaCl), and HS+CM diet (0.1% CM) groups. After weekly blood pressure measurement and 24-h urine collection, the rats were sacrificed at 5 weeks. The HS group exhibited hypertension, massive proteinuria, increased urinary plasmin, and γENaC activation; CM treatment suppressed these changes. CM prevented plasmin(ogen) attachment to podocytes and mitigated podocyte injury by reducing the number of apoptotic glomerular cells, inhibiting protease-activated receptor-1 activation, and suppressing inflammatory and fibrotic cytokine expression. Our findings highlight the detrimental role of urinary plasmin in the pathogenesis of salt-sensitive hypertension and glomerular injury. Targeting plasmin with SP inhibitors, such as CM, may be a promising therapeutic approach for these conditions. Full article

(This article belongs to the Special Issue The Role of Protease and Protease Inhibitors in Human Diseases)

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Review

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37 pages, 3370 KiB

Open AccessReview

The Lectin Pathway of the Complement System—Activation, Regulation, Disease Connections and Interplay with Other (Proteolytic) Systems

by József Dobó, Andrea Kocsis, Bence Farkas, Flóra Demeter, László Cervenak and Péter Gál

Int. J. Mol. Sci. 2024, 25(3), 1566; https://doi.org/10.3390/ijms25031566 - 26 Jan 2024

Cited by 20 | Viewed by 7950

Abstract

The complement system is the other major proteolytic cascade in the blood of vertebrates besides the coagulation–fibrinolytic system. Among the three main activation routes of complement, the lectin pathway (LP) has been discovered the latest, and it is still the subject of intense research. Mannose-binding lectin (MBL), other collectins, and ficolins are collectively termed as the pattern recognition molecules (PRMs) of the LP, and they are responsible for targeting LP activation to molecular patterns, e.g., on bacteria. MBL-associated serine proteases (MASPs) are the effectors, while MBL-associated proteins (MAps) have regulatory functions. Two serine protease components, MASP-1 and MASP-2, trigger the LP activation, while the third component, MASP-3, is involved in the function of the alternative pathway (AP) of complement. Besides their functions within the complement system, certain LP components have secondary (“moonlighting”) functions, e.g., in embryonic development. They also contribute to blood coagulation, and some might have tumor suppressing roles. Uncontrolled complement activation can contribute to the progression of many diseases (e.g., stroke, kidney diseases, thrombotic complications, and COVID-19). In most cases, the lectin pathway has also been implicated. In this review, we summarize the history of the lectin pathway, introduce their components, describe its activation and regulation, its roles within the complement cascade, its connections to blood coagulation, and its direct cellular effects. Special emphasis is placed on disease connections and the non-canonical functions of LP components. Full article

(This article belongs to the Special Issue The Role of Protease and Protease Inhibitors in Human Diseases)

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