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International Journal of Molecular... Feb 2021The deepest evolutionary branches of the trypsin/chymotrypsin family of serine proteases are represented by the digestive enzymes of the gastrointestinal tract and the... (Review)
Review
The deepest evolutionary branches of the trypsin/chymotrypsin family of serine proteases are represented by the digestive enzymes of the gastrointestinal tract and the multi-domain proteases of the blood coagulation and complement system. Similar to the very old digestive system, highly diverse cleavage specificities emerged in various cell lineages of the immune defense system during vertebrate evolution. The four neutrophil serine proteases (NSPs) expressed in the myelomonocyte lineage, neutrophil elastase, proteinase 3, cathepsin G, and neutrophil serine protease 4, collectively display a broad repertoire of (S1) specificities. The origin of NSPs can be traced back to a circulating liver-derived trypsin-like protease, the complement factor D ancestor, whose activity is tightly controlled by substrate-induced activation and TNFα-induced locally upregulated protein secretion. However, the present-day descendants are produced and converted to mature enzymes in precursor cells of the bone marrow and are safely sequestered in granules of circulating neutrophils. The potential site and duration of action of these cell-associated serine proteases are tightly controlled by the recruitment and activation of neutrophils, by stimulus-dependent regulated secretion of the granules, and by various soluble inhibitors in plasma, interstitial fluids, and in the inflammatory exudate. An extraordinary dynamic range and acceleration of immediate defense responses have been achieved by exploiting the high structural plasticity of the trypsin fold.
Topics: Animals; Cathepsin G; Cell Lineage; Humans; Leukocyte Elastase; Monocytes; Myeloblastin; Myeloid Cells; Serine Proteases
PubMed: 33562184
DOI: 10.3390/ijms22041658 -
Epigenetics Mar 2021Coronavirus disease 2019 (COVID-2019) outbreak originating in December 2019 in Wuhan, China has emerged as a global threat to human health. The highly contagious... (Review)
Review
Coronavirus disease 2019 (COVID-2019) outbreak originating in December 2019 in Wuhan, China has emerged as a global threat to human health. The highly contagious SARS-CoV-2 infection and transmission presents a diversity of human host and increased disease risk with advancing age, highlighting the importance of in-depth understanding of its biological properties. Structural analyses have elucidated hot spots in viral binding domains, mutations, and specific proteins in the host such as the receptor angiotensin-converting enzyme 2 (ACE2) and the transmembrane protease serine 2 (TMPRSS2) to be implicated in cell entry and viral infectivity. Furthermore, epigenetic changes that regulate chromatin structure have shown a major impact in genome stabilization and maintenance of cellular homoeostasis and they have been implicated in the pathophysiology of the virus infection. Epigenetic research has revealed that global DNA methylation along with gene methylation and post-translational histone modifications may drive differences in host tissue-, biological age- and sex-biased patterns of viral infection. Moreover, modulation of the host cells epigenetic landscape following infection represents a molecular tool used by viruses to antagonize cellular signalling as well as sensing components that regulate the induction of the host innate immune and antiviral defence programmes in order to enhance viral replication and infection efficiency. In this review, we provide an update of the main research findings at the interface of epigenetics and coronavirus infection. In particular, we highlight the epigenetic factors that interfere with viral replication and infection and may contribute to COVID-19 susceptibility, offering new ways of thinking in respect to host viral response.
Topics: Angiotensin-Converting Enzyme 2; COVID-19; Epigenesis, Genetic; Gene Expression Regulation, Viral; Humans; SARS-CoV-2; Serine Endopeptidases
PubMed: 32686577
DOI: 10.1080/15592294.2020.1796896 -
Science Advances Dec 2023Melanization and Toll pathway activation are essential innate immune mechanisms in insects, which result in the generation of reactive compounds and antimicrobial...
Melanization and Toll pathway activation are essential innate immune mechanisms in insects, which result in the generation of reactive compounds and antimicrobial peptides, respectively, to kill pathogens. These two processes are mediated by phenoloxidase (PO) and Spätzle (Spz) through an extracellular network of serine proteases. While some proteases have been identified in in genetic studies, the exact order of proteolytic activation events remains controversial. Here, we reconstituted the serine protease framework in by biochemical methods. This system comprises 10 proteases, i.e., ModSP, cSP48, Grass, Psh, Hayan-PA, Hayan-PB, Sp7, MP1, SPE and Ser7, which form cascade pathways that recognize microbial molecular patterns and virulence factors, and generate PO1, PO2, and Spz from their precursors. Furthermore, the serpin Necrotic negatively regulates the immune response progression by inhibiting ModSP and Grass. The biochemical approach, when combined with genetic analysis, is crucial for addressing problems that long stand in this important research field.
Topics: Animals; Drosophila; Drosophila melanogaster; Drosophila Proteins; Serine Endopeptidases; Serine Proteases
PubMed: 38117884
DOI: 10.1126/sciadv.adk2756 -
Journal of Medical Virology Jul 2021Epidemiological data shows a discrepancy in COVID-19 susceptibility and outcomes with some regions being more heavily affected than others. However, the factors that... (Review)
Review
Epidemiological data shows a discrepancy in COVID-19 susceptibility and outcomes with some regions being more heavily affected than others. However, the factors that determine host susceptibility and pathogenicity remain elusive. An increasing number of publications highlight the role of Transmembrane Serine Protease 2 (TMPRSS2) in the susceptibility of the host cell to SARS-CoV-2. Cleavage of viral spike protein via the host cell's TMPRSS2 enzyme activity mediates viral entry into the host cell. The enzyme synthesis is regulated by the TMPRSS2 gene, which has also been implicated in the entry mechanisms of previously reported Coronavirus infections. In this review, we have investigated the pathogenicity of SARS-CoV-2 and disease susceptibility dependence on the TMPRSS2 gene as expressed in various population groups. We further discuss how the differential expression of this gene in various ethnic groups can affect the SARS-CoV-2 infection and Coronavirus disease (COVID)-19 outcomes. Moreover, promising new TMPRSS2 protease blockers and inhibitors are discussed for COVID-19 treatment.
Topics: Anosmia; COVID-19; Female; Genetic Predisposition to Disease; Humans; Male; SARS-CoV-2; Serine Endopeptidases; Spike Glycoprotein, Coronavirus; Virus Internalization; COVID-19 Drug Treatment
PubMed: 33638460
DOI: 10.1002/jmv.26911 -
Arthritis Research & Therapy Jun 2023High-temperature requirement serine protease A 2 (HtrA2) is known to be involved in growth, unfolded protein response to stress, apoptosis, and autophagy. However,...
BACKGROUND
High-temperature requirement serine protease A 2 (HtrA2) is known to be involved in growth, unfolded protein response to stress, apoptosis, and autophagy. However, whether HtrA2 controls inflammation and immune response remains elusive.
METHODS
Expression of HtrA2 in the synovial tissue of patients was examined using immunohistochemistry and immunofluorescence staining. Enzyme-linked immunosorbent assay was used to determine the concentrations of HtrA2, interleukin-6 (IL-6), interleukin-8 (IL-8), chemokine (C-C motif) ligand 2 (CCL2), and tumor necrosis factor α (TNFα). Synoviocyte survival was assessed by MTT assay. For the downregulation of HtrA2 transcripts, cells were transfected with HtrA2 siRNA.
RESULTS
We found that the concentration of HtrA2 was elevated in rheumatoid arthritis (RA) synovial fluid (SF) than in osteoarthritis (OA) SF, and its concentrations were correlated with the number of immune cells in the RA SF. Interestingly, HtrA2 levels in the SF of RA patients were elevated in proportion to synovitis severity and correlated with the expression of proinflammation cytokines and chemokines, such as IL-6, IL-8, and CCL2. In addition, HtrA2 was highly expressed in RA synovium and primary synoviocytes. RA synoviocytes released HtrA2 when stimulated with ER stress inducers. Knockdown of HtrA2 inhibited the IL1β-, TNFα-, and LPS-induced release of proinflammatory cytokines and chemokines by RA synoviocytes.
CONCLUSION
HtrA2 is a novel inflammatory mediator and a potential target for the development of an anti-inflammation therapy for RA.
Topics: Humans; Arthritis, Rheumatoid; Cells, Cultured; Chemokines; Cytokines; Fibroblasts; Inflammation; Interleukin-6; Interleukin-8; Serine Endopeptidases; Serine Proteases; Synovial Membrane; Synoviocytes; Temperature; Tumor Necrosis Factor-alpha
PubMed: 37287073
DOI: 10.1186/s13075-023-03081-z -
Frontiers in Immunology 2022During tumor development, invasion and metastasis, the intimate interaction between tumor and stroma shapes the tumor microenvironment and dictates the fate of tumor... (Review)
Review
During tumor development, invasion and metastasis, the intimate interaction between tumor and stroma shapes the tumor microenvironment and dictates the fate of tumor cells. Stromal cells can also influence anti-tumor immunity and response to immunotherapy. Understanding the molecular mechanisms that govern this complex and dynamic interplay, thus is important for cancer diagnosis and therapy. Proteolytic enzymes that are expressed and secreted by both cancer and stromal cells play important roles in modulating tumor-stromal interaction. Among, several serine proteases such as fibroblast activation protein, urokinase-type plasminogen activator, kallikrein-related peptidases, and granzymes have attracted great attention owing to their elevated expression and dysregulated activity in the tumor microenvironment. This review highlights the role of serine proteases that are mainly derived from stromal cells in tumor progression and associated theranostic applications.
Topics: Animals; Carcinogenesis; Endopeptidases; Extracellular Matrix; Granzymes; Humans; Kallikreins; Membrane Proteins; Neoplasms; Precision Medicine; Serine Proteases; Stromal Cells; Tumor Microenvironment; Urokinase-Type Plasminogen Activator
PubMed: 35222418
DOI: 10.3389/fimmu.2022.832418 -
Biomolecules Sep 2023Serine protease inhibitors, SERPINS, are a highly conserved family of proteins that regulate serine proteases in the central coagulation and immune pathways,... (Review)
Review
Serine protease inhibitors, SERPINS, are a highly conserved family of proteins that regulate serine proteases in the central coagulation and immune pathways, representing 2-10% of circulating proteins in the blood. Serine proteases form cascades of sequentially activated enzymes that direct thrombosis (clot formation) and thrombolysis (clot dissolution), complement activation in immune responses and also programmed cell death (apoptosis). Virus-derived serpins have co-evolved with mammalian proteases and serpins, developing into highly effective inhibitors of mammalian proteolytic pathways. Through interacting with extracellular and intracellular serine and cysteine proteases, viral serpins provide a new class of highly active virus-derived coagulation-, immune-, and apoptosis-modulating drug candidates. Viral serpins have unique characteristics: (1) function at micrograms per kilogram doses; (2) selectivity in targeting sites of protease activation; (3) minimal side effects at active concentrations; and (4) the demonstrated capacity to be modified, or fine-tuned, for altered protease targeting. To date, the virus-derived serpin class of biologics has proven effective in a wide range of animal models and in one clinical trial in patients with unstable coronary disease. Here, we outline the known viral serpins and review prior studies with viral serpins, considering their potential for application as new sources for immune-, coagulation-, and apoptosis-modulating therapeutics.
Topics: Animals; Humans; Serpins; Serine Proteinase Inhibitors; Serine Endopeptidases; Serine Proteases; Mammals
PubMed: 37759793
DOI: 10.3390/biom13091393 -
The FEBS Journal Sep 2021Cell membrane-bound serine proteases are important in the maintenance of physiological homeostasis. Hepsin is a type II transmembrane serine protease highly expressed in... (Review)
Review
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.
Topics: Adipose Tissue; Animals; Cell Differentiation; Gene Expression Regulation; Hepatocyte Growth Factor; Homeostasis; Humans; Kidney; Liver; Mice; Neoplasms; Proto-Oncogene Proteins c-met; Serine Endopeptidases; Serine Proteases
PubMed: 33300264
DOI: 10.1111/febs.15663 -
Frontiers in Cellular and Infection... 2021The pathobiont causes life-threatening diseases, including pneumonia, sepsis, meningitis, or non-invasive infections such as otitis media. Serine proteases are enzymes... (Review)
Review
The pathobiont causes life-threatening diseases, including pneumonia, sepsis, meningitis, or non-invasive infections such as otitis media. Serine proteases are enzymes that have been emerged during evolution as one of the most abundant and functionally diverse group of proteins in eukaryotic and prokaryotic organisms. expresses up to four extracellular serine proteases belonging to the category of trypsin-like or subtilisin-like family proteins: HtrA, SFP, PrtA, and CbpG. These serine proteases have recently received increasing attention because of their immunogenicity and pivotal role in the interaction with host proteins. This review is summarizing and focusing on the molecular and functional analysis of pneumococcal serine proteases, thereby discussing their contribution to pathogenesis.
Topics: Humans; Otitis Media; Pneumococcal Infections; Serine Endopeptidases; Streptococcus pneumoniae; Subtilisin; Trypsin
PubMed: 34790590
DOI: 10.3389/fcimb.2021.763152 -
Advanced Science (Weinheim,... Sep 2023Cigarette smoke aggravates severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, the underlying mechanisms remain unclear. Here, they show...
Cigarette smoke aggravates severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, the underlying mechanisms remain unclear. Here, they show that benzo[a]pyrene in cigarette smoke extract facilitates SARS-CoV-2 infection via upregulating angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2). Benzo[a]pyrene trans-activates the promoters of ACE2 and TMPRSS2 by upregulating nuclear receptor subfamily 4 A number 2 (NR4A2) and promoting its binding of NR4A2 to their promoters, which is independent of functional genetic polymorphisms in ACE2 and TMPRSS2. Benzo[a]pyrene increases the susceptibility of lung epithelial cells to SARS-CoV-2 pseudoviruses and facilitates the infection of authentic Omicron BA.5 in primary human alveolar type II cells, lung organoids, and lung and testis of hamsters. Increased expression of Nr4a2, Ace2, and Tmprss2, as well as decreased methylation of CpG islands at the Nr4a2 promoter are observed in aged mice compared to their younger counterparts. NR4A2 knockdown or interferon-λ2/λ3 stimulation downregulates the expression of NR4A2, ACE2, and TMPRSS2, thereby inhibiting the infection. In conclusion, benzo[a]pyrene enhances SARS-CoV-2 infection by boosting NR4A2-induced ACE2 and TMPRSS2 expression. This study elucidates the mechanisms underlying the detrimental effects of cigarette smoking on SARS-CoV-2 infection and provides prophylactic options for coronavirus disease 2019, particularly for the elderly population.
Topics: Aged; Male; Humans; Animals; Mice; COVID-19; SARS-CoV-2; Angiotensin-Converting Enzyme 2; Benzo(a)pyrene; Lung; Nuclear Receptor Subfamily 4, Group A, Member 2; Serine Endopeptidases
PubMed: 37428471
DOI: 10.1002/advs.202300834