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Lysosomal Proteases and Their Inhibitors
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Lysosomal Proteases and Their Inhibitors

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Macromolecules".

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 15680

Special Issue Editors

Prof. Dr. Vito Turk

E-Mail Website
Guest Editor
Department of Biochemistry and Molecular and Structural Biology, Jozef Stefan Institute, SI-1000 Ljubljana, Slovenia
Interests: lysosomal proteases; cathepsins; protein and small Mw inhibitors; cystatins, structure and function of proteases; MHC-II antigen presentation and role of proteases; biochemical characterization of proteins
Prof. Dr. Veronika Stoka

E-Mail Website
Guest Editor
Department of Biochemistry and Molecular and Structural Biology, Jozef Stefan Institute, SI-1000 Ljubljana, Slovenia
Interests: aging; neurodegeneration; neurodegenerative diseases; cysteine cathepsins; cystatins

Special Issue Information

Dear Colleagues,

The discovery of the lysosome, a major cytoplasmic organelle, represents a significant breakthrough in the understanding of intracellular protein degradation processes—proteolysis. Lysosomes contain over fifty hydrolases. Among them, proteases, especially  cathepsins, are involved in a broad spectrum of biological functions. Cathepsins are separated into three different catalytic types: serine proteases (cathepsins A and G), aspartic proteases (cathepsin D and E), and cysteine proteases (cathepsins B, C, F, H, K, L, O, S, V, X/Z and W). They are generally well-characterized enzymes with optimal  activity at slightly acidic environments, although some of them retain enzymatic activity at a higher pH, which is important for their extracellular function outside of the endo-lysosomal system. They are involved in many physiological and pathological processes. Their potentially harmful activity outside the lysosomes must be regulated by pH, and their endogenous protein inhibitors cystatins, thyropins, and others, including small-molecule synthetic inhibitors. This Special issue will cover recent advances toward a better understanding of proteolysis and its control mechanisms: structural aspects, bioinformatic analysis of human and other genomes, proteomics, and  recently developed advanced methods such as drug targeting, selective labeling, and visualization. These and other approaches will contribute to a further understanding of cancer, cardiovascular diseases, neurodegeneration, and other diseases.

Prof. Dr. Vito Turk
Prof. Dr. Veronika Stoka
Guest Editors

Manuscript Submission Information

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Keywords

  • lysosomal proteases
  • cathepsins
  • inhibitors
  • cystatins
  • proteolysis
  • diseases

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Published Papers (6 papers)

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Editorial

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3 pages, 170 KiB  
Editorial
Lysosomal Proteases and Their Inhibitors
by Vito Turk and Veronika Stoka
Int. J. Mol. Sci. 2024, 25(18), 10070; https://doi.org/10.3390/ijms251810070 - 19 Sep 2024
Viewed by 744
Abstract
The discovery of the lysosome, a major cytoplasmic organelle, represents a breakthrough in the understanding of intracellular protein degradation processes—proteolysis [...] Full article
(This article belongs to the Special Issue Lysosomal Proteases and Their Inhibitors)

Research

Jump to: Editorial, Review

17 pages, 1927 KiB  
Article
Origin and Early Diversification of the Papain Family of Cysteine Peptidases
by Dušan Kordiš and Vito Turk
Int. J. Mol. Sci. 2023, 24(14), 11761; https://doi.org/10.3390/ijms241411761 - 21 Jul 2023
Cited by 4 | Viewed by 1551
Abstract
Peptidases of the papain family play a key role in protein degradation, regulated proteolysis, and the host–pathogen arms race. Although the papain family has been the subject of many studies, knowledge about its diversity, origin, and evolution in Eukaryota, Bacteria, and Archaea is [...] Read more.
Peptidases of the papain family play a key role in protein degradation, regulated proteolysis, and the host–pathogen arms race. Although the papain family has been the subject of many studies, knowledge about its diversity, origin, and evolution in Eukaryota, Bacteria, and Archaea is limited; thus, we aimed to address these long-standing knowledge gaps. We traced the origin and expansion of the papain family with a phylogenomic analysis, using sequence data from numerous prokaryotic and eukaryotic proteomes, transcriptomes, and genomes. We identified the full complement of the papain family in all prokaryotic and eukaryotic lineages. Analysis of the papain family provided strong evidence for its early diversification in the ancestor of eukaryotes. We found that the papain family has undergone complex and dynamic evolution through numerous gene duplications, which produced eight eukaryotic ancestral paralogous C1A lineages during eukaryogenesis. Different evolutionary forces operated on C1A peptidases, including gene duplication, horizontal gene transfer, and gene loss. This study challenges the current understanding of the origin and evolution of the papain family and provides valuable insights into their early diversification. The findings of this comprehensive study provide guidelines for future structural and functional studies of the papain family. Full article
(This article belongs to the Special Issue Lysosomal Proteases and Their Inhibitors)
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15 pages, 2673 KiB  
Article
Legumain Functions as a Transient TrkB Sheddase
by Christoph Holzner, Katharina Böttinger, Constantin Blöchl, Christian G. Huber, Sven O. Dahms, Elfriede Dall and Hans Brandstetter
Int. J. Mol. Sci. 2023, 24(6), 5394; https://doi.org/10.3390/ijms24065394 - 11 Mar 2023
Cited by 1 | Viewed by 1853
Abstract
While primarily found in endo-lysosomal compartments, the cysteine protease legumain can also translocate to the cell surface if stabilized by the interaction with the RGD-dependent integrin receptor αVβ3. Previously, it has been shown that legumain expression is inversely related to BDNF-TrkB activity. Here [...] Read more.
While primarily found in endo-lysosomal compartments, the cysteine protease legumain can also translocate to the cell surface if stabilized by the interaction with the RGD-dependent integrin receptor αVβ3. Previously, it has been shown that legumain expression is inversely related to BDNF-TrkB activity. Here we show that legumain can conversely act on TrkB-BDNF by processing the C-terminal linker region of the TrkB ectodomain in vitro. Importantly, when in complex with BDNF, TrkB was not cleaved by legumain. Legumain-processed TrkB was still able to bind BDNF, suggesting a potential scavenger function of soluble TrkB towards BDNF. The work thus presents another mechanistic link explaining the reciprocal TrkB signaling and δ-secretase activity of legumain, with relevance for neurodegeneration. Full article
(This article belongs to the Special Issue Lysosomal Proteases and Their Inhibitors)
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Review

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15 pages, 1177 KiB  
Review
Tick Salivary Kunitz-Type Inhibitors: Targeting Host Hemostasis and Immunity to Mediate Successful Blood Feeding
by Mohamed Amine Jmel, Hanne Voet, Ricardo N. Araújo, Lucas Tirloni, Anderson Sá-Nunes and Michail Kotsyfakis
Int. J. Mol. Sci. 2023, 24(2), 1556; https://doi.org/10.3390/ijms24021556 - 13 Jan 2023
Cited by 15 | Viewed by 3018
Abstract
Kunitz domain-containing proteins are ubiquitous serine protease inhibitors with promising therapeutic potential. They target key proteases involved in major cellular processes such as inflammation or hemostasis through competitive inhibition in a substrate-like manner. Protease inhibitors from the Kunitz superfamily have a low molecular [...] Read more.
Kunitz domain-containing proteins are ubiquitous serine protease inhibitors with promising therapeutic potential. They target key proteases involved in major cellular processes such as inflammation or hemostasis through competitive inhibition in a substrate-like manner. Protease inhibitors from the Kunitz superfamily have a low molecular weight (18–24 kDa) and are characterized by the presence of one or more Kunitz motifs consisting of α-helices and antiparallel β-sheets stabilized by three disulfide bonds. Kunitz-type inhibitors are an important fraction of the protease inhibitors found in tick saliva. Their roles in inhibiting and/or suppressing host homeostatic responses continue to be shown to be additive or synergistic with other protease inhibitors such as cystatins or serpins, ultimately mediating successful blood feeding for the tick. In this review, we discuss the biochemical features of tick salivary Kunitz-type protease inhibitors. We focus on their various effects on host hemostasis and immunity at the molecular and cellular level and their potential therapeutic applications. In doing so, we highlight that their pharmacological properties can be exploited for the development of novel therapies and vaccines. Full article
(This article belongs to the Special Issue Lysosomal Proteases and Their Inhibitors)
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17 pages, 1424 KiB  
Review
Cathepsin K in Pathological Conditions and New Therapeutic and Diagnostic Perspectives
by Olja Mijanović, Aleksandra Jakovleva, Ana Branković, Kristina Zdravkova, Milena Pualic, Tatiana A. Belozerskaya, Angelina I. Nikitkina, Alessandro Parodi and Andrey A. Zamyatnin, Jr.
Int. J. Mol. Sci. 2022, 23(22), 13762; https://doi.org/10.3390/ijms232213762 - 9 Nov 2022
Cited by 17 | Viewed by 3657
Abstract
Cathepsin K (CatK) is a part of the family of cysteine proteases involved in many important processes, including the degradation activity of collagen 1 and elastin in bone resorption. Changes in levels of CatK are associated with various pathological conditions, primarily related to [...] Read more.
Cathepsin K (CatK) is a part of the family of cysteine proteases involved in many important processes, including the degradation activity of collagen 1 and elastin in bone resorption. Changes in levels of CatK are associated with various pathological conditions, primarily related to bone and cartilage degradation, such as pycnodysostosis (associated with CatK deficiency), osteoporosis, and osteoarthritis (associated with CatK overexpression). Recently, the increased secretion of CatK is being highly correlated to vascular inflammation, hypersensitivity pneumonitis, Wegener granulomatosis, berylliosis, tuberculosis, as well as with tumor progression. Due to the wide spectrum of diseases in which CatK is involved, the design and validation of active site-specific inhibitors has been a subject of keen interest in pharmaceutical companies in recent decades. In this review, we summarized the molecular background of CatK and its involvement in various diseases, as well as its clinical significance for diagnosis and therapy. Full article
(This article belongs to the Special Issue Lysosomal Proteases and Their Inhibitors)
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17 pages, 803 KiB  
Review
The Key Role of Lysosomal Protease Cathepsins in Viral Infections
by Melania Scarcella, Danila d’Angelo, Mariangela Ciampa, Simona Tafuri, Luigi Avallone, Luigi Michele Pavone and Valeria De Pasquale
Int. J. Mol. Sci. 2022, 23(16), 9089; https://doi.org/10.3390/ijms23169089 - 13 Aug 2022
Cited by 29 | Viewed by 3715
Abstract
Cathepsins encompass a family of lysosomal proteases that mediate protein degradation and turnover. Although mainly localized in the endolysosomal compartment, cathepsins are also found in the cytoplasm, nucleus, and extracellular space, where they are involved in cell signaling, extracellular matrix assembly/disassembly, and protein [...] Read more.
Cathepsins encompass a family of lysosomal proteases that mediate protein degradation and turnover. Although mainly localized in the endolysosomal compartment, cathepsins are also found in the cytoplasm, nucleus, and extracellular space, where they are involved in cell signaling, extracellular matrix assembly/disassembly, and protein processing and trafficking through the plasma and nuclear membrane and between intracellular organelles. Ubiquitously expressed in the body, cathepsins play regulatory roles in a wide range of physiological processes including coagulation, hormone secretion, immune responses, and others. A dysregulation of cathepsin expression and/or activity has been associated with many human diseases, including cancer, diabetes, obesity, cardiovascular and inflammatory diseases, kidney dysfunctions, and neurodegenerative disorders, as well as infectious diseases. In viral infections, cathepsins may promote (1) activation of the viral attachment glycoproteins and entry of the virus into target cells; (2) antigen processing and presentation, enabling the virus to replicate in infected cells; (3) up-regulation and processing of heparanase that facilitates the release of viral progeny and the spread of infection; and (4) activation of cell death that may either favor viral clearance or assist viral propagation. In this review, we report the most relevant findings on the molecular mechanisms underlying cathepsin involvement in viral infection physiopathology, and we discuss the potential of cathepsin inhibitors for therapeutical applications in viral infectious diseases. Full article
(This article belongs to the Special Issue Lysosomal Proteases and Their Inhibitors)
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