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Frontiers in Immunology 2022CD95L (also known as FasL or CD178) is a member of the tumor necrosis family (TNF) superfamily. Although this transmembrane ligand has been mainly considered as a potent... (Review)
Review
CD95L (also known as FasL or CD178) is a member of the tumor necrosis family (TNF) superfamily. Although this transmembrane ligand has been mainly considered as a potent apoptotic inducer in CD95 (Fas)-expressing cells, more recent studies pointed out its role in the implementation of non-apoptotic signals. Accordingly, this ligand has been associated with the aggravation of inflammation in different auto-immune disorders and in the metastatic occurrence in different cancers. Although it remains to decipher all key factors involved in the ambivalent role of this ligand, accumulating clues suggest that while the membrane bound CD95L triggers apoptosis, its soluble counterpart generated by metalloprotease-driven cleavage is responsible for its non-apoptotic functions. Nonetheless, the metalloproteases (MMPs and ADAMs) involved in the CD95L shedding, the cleavage sites and the different stoichiometries and functions of the soluble CD95L remain to be elucidated. To better understand how soluble CD95L triggers signaling pathways from apoptosis to inflammation or cell migration, we propose herein to summarize the different metalloproteases that have been described to be able to shed CD95L, their cleavage sites and the biological functions associated with the released ligands. Based on these new findings, the development of CD95/CD95L-targeting therapeutics is also discussed.
Topics: Humans; Fas Ligand Protein; Ligands; fas Receptor; Metalloproteases; Signal Transduction; Neoplasms; Inflammation
PubMed: 36544756
DOI: 10.3389/fimmu.2022.1074099 -
Toxins Jan 2020The active components of snake venoms encompass a complex and variable mixture of proteins that produce a diverse, but largely stereotypical, range of pharmacologic... (Review)
Review
The active components of snake venoms encompass a complex and variable mixture of proteins that produce a diverse, but largely stereotypical, range of pharmacologic effects and toxicities. Venom protein diversity and host susceptibilities determine the relative contributions of five main pathologies: neuromuscular dysfunction, inflammation, coagulopathy, cell/organ injury, and disruption of homeostatic mechanisms of normal physiology. In this review, we describe how snakebite is not only a condition mediated directly by venom, but by the amplification of signals dysregulating inflammation, coagulation, neurotransmission, and cell survival. Although venom proteins are diverse, the majority of important pathologic events following envenoming follow from a small group of enzyme-like activities and the actions of small toxic peptides. This review focuses on two of the most important enzymatic activities: snake venom phospholipases (svPLA) and snake venom metalloproteases (svMP). These two enzyme classes are adept at enabling venom to recruit homologous endogenous signaling systems with sufficient magnitude and duration to produce and amplify cell injury beyond what would be expected from the direct impact of a whole venom dose. This magnification produces many of the most acutely important consequences of envenoming as well as chronic sequelae. Snake venom PLAs and MPs enzymes recruit prey analogs of similar activity. The transduction mechanisms that recruit endogenous responses include arachidonic acid, intracellular calcium, cytokines, bioactive peptides, and possibly dimerization of venom and prey protein homologs. Despite years of investigation, the precise mechanism of svPLA-induced neuromuscular paralysis remains incomplete. Based on recent studies, paralysis results from a self-amplifying cycle of endogenous PLA activation, arachidonic acid, increases in intracellular Ca and nicotinic receptor deactivation. When prolonged, synaptic suppression supports the degeneration of the synapse. Interaction between endothelium-damaging MPs, sPLAs and hyaluronidases enhance venom spread, accentuating venom-induced neurotoxicity, inflammation, coagulopathy and tissue injury. Improving snakebite treatment requires new tools to understand direct and indirect effects of envenoming. Homologous PLA and MP activities in both venoms and prey/snakebite victim provide molecular targets for non-antibody, small molecule agents for dissecting mechanisms of venom toxicity. Importantly, these tools enable the separation of venom-specific and prey-specific pathological responses to venom.
Topics: Animals; Blood Coagulation; Humans; Inflammation; Metalloproteases; Phospholipases A2, Secretory; Reptilian Proteins; Signal Transduction; Snake Venoms
PubMed: 31979014
DOI: 10.3390/toxins12020068 -
Chemosphere Mar 2021Venom geographical variation is common among venomous animals. This phenomenon presents problems in the development of clinical treatments and medicines against...
Venom geographical variation is common among venomous animals. This phenomenon presents problems in the development of clinical treatments and medicines against envenomation. The venomous giant jellyfish Nemopilema nomurai, Scyphozoan, is a blooming jellyfish species in the Yellow Sea and the East China Sea that causes numerous jellyfish sting cases every year. Metalloprotease and phospholipase A (PLA) are the main components in Nemopilema nomurai venom and may activate many toxicities, such as hemolysis, inflammation and lethality. Geographical variation in the content and activity of these enzymes may cause different symptoms and therapeutic problems. For the first time, we verified metalloprotease and PLA geographical variation in Nemopilema nomurai venom by performing a comparative analysis of 31 venom samples by SDS-PAGE, analyzing protease zymography, enzymatic activity, and drawing contour maps. Band locations and intensities of SDS-PAGE and protease zymograms showed geographical differences. The enzymatic activities of both metalloprotease and PLA showed a trend of geographic regularity. The distribution patterns of these activities are directly shown in contour maps. Metalloproteinase activity was lower near the coast. PLA-like activity was lower in the Southern Yellow Sea. We surmised that metalloproteinase and PLA-like activities might be related to venom ontogeny and species abundance respectively, and influenced by similar environmental factors. This study provides a theoretical basis for further ecological and medical studies of Nemopilema nomurai jellyfish venom.
Topics: Animals; China; Cnidarian Venoms; Metalloproteases; Phospholipases; Scyphozoa
PubMed: 33310516
DOI: 10.1016/j.chemosphere.2020.129164 -
Cancer Metastasis Reviews Sep 2019A crucial step for tumor cell extravasation and metastasis is the migration through the extracellular matrix, which requires proteolytic activity. Hence, proteases,... (Review)
Review
A crucial step for tumor cell extravasation and metastasis is the migration through the extracellular matrix, which requires proteolytic activity. Hence, proteases, particularly matrix metalloproteases (MMPs), have been discussed as therapeutic targets and their inhibition should diminish tumor growth and metastasis. The metalloproteases meprin α and meprin β are highly abundant on intestinal enterocytes and their expression was associated with different stages of colorectal cancer. Due to their ability to cleave extracellular matrix (ECM) components, they were suggested as pro-tumorigenic enzymes. Additionally, both meprins were shown to have pro-inflammatory activity by cleaving cytokines and their receptors, which correlates with chronic intestinal inflammation and associated conditions. On the other hand, meprin β was identified as an essential enzyme for the detachment and renewal of the intestinal mucus, important to prevent bacterial overgrowth and infection. Considering this, it is hard to estimate whether high activity of meprins is generally detrimental or if these enzymes have also protective functions in certain cancer types. For instance, for colorectal cancer, patients with high meprin β expression in tumor tissue exhibit a better survival prognosis, which is completely different to prostate cancer. This demonstrates that the very same enzyme may have contrary effects on tumor initiation and growth, depending on its tissue and subcellular localization. Hence, precise knowledge about proteolytic enzymes is required to design the most efficient therapeutic options for cancer treatment. In this review, we summarize the current findings on meprins' functions, expression, and cancer-associated variants with possible implications for tumor progression and metastasis.
Topics: Animals; Humans; Metalloendopeptidases; Neoplasm Metastasis; Neoplasms; Tumor Microenvironment
PubMed: 31482488
DOI: 10.1007/s10555-019-09805-5 -
Cytokine Feb 2019Meprin metalloendopeptidases, comprising α and β isoforms, are widely expressed in mammalian cells and organs including kidney, intestines, lungs, skin, and bladder,... (Review)
Review
Meprin metalloendopeptidases, comprising α and β isoforms, are widely expressed in mammalian cells and organs including kidney, intestines, lungs, skin, and bladder, and in a variety of immune cells and cancer cells. Meprins proteolytically process many inflammatory mediators, including cytokines, chemokines, and other bioactive proteins and peptides that control the function of immune cells. The knowledge of meprin-mediated processing of inflammatory mediators and other target substrates provides a pathophysiologic link for the involvement of meprins in the pathogenesis of many inflammatory disorders. Meprins are now known to play important roles in inflammatory diseases including acute kidney injury, sepsis, urinary tract infections, bladder inflammation, and inflammatory bowel disease. The proteolysis of epithelial and endothelial barriers including cell junctional proteins by meprins promotes leukocyte influx into areas of tissue damage to result in inflammation. Meprins degrade extracellular matrix proteins; this ability of meprins is implicated in the cell migration of leukocytes and the invasion of tumor cells that express meprins. Proteolytic processing and maturation of procollagens provides evidence that meprins are involved in collagen maturation and deposition in the fibrotic processes involved in the formation of keloids and hypertrophic scars and lung fibrosis. This review highlights recent progress in understanding the role of meprins in inflammatory disorders in both human and mouse models.
Topics: Amino Acid Sequence; Animals; Cytokines; Extracellular Matrix Proteins; Humans; Inflammation; Metalloproteases; Proteolysis
PubMed: 30580156
DOI: 10.1016/j.cyto.2018.11.032 -
General and Comparative Endocrinology Jan 2023Development of a functional gonad includes migration of primordial germ cells (PGCs), differentiations of somatic and germ cells, formation of primary follicles or...
Development of a functional gonad includes migration of primordial germ cells (PGCs), differentiations of somatic and germ cells, formation of primary follicles or spermatogenic cysts with somatic gonadal cells, development and maturation of gametes, and subsequent releasing of mature germ cells. These processes require extensive cellular and tissue remodeling, as well as broad alterations of the surrounding extracellular matrix (ECM). Metalloproteases, including MMPs (matrix metalloproteases), ADAMs (a disintegrin and metalloproteinases), and ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs), are suggested to have critical roles in the remodeling of the ECM during gonad development. However, few research articles and reviews are available on the functions and mechanisms of metalloproteases in remodeling gonadal ECM, gonadal development, or gonadal differentiation. Moreover, most studies focused on the roles of transcription and growth factors in early gonad development and primary sex determination, leaving a significant knowledge gap on how differentially expressed metalloproteases exert effects on the ECM, cell migration, development, and survival of germ cells during the development and differentiation of ovaries or testes. We will review gonad development with focus on the evidence of metalloprotease involvements, and with an emphasis on zebrafish as a model for studying gonadal sex differentiation and metalloprotease functions.
Topics: Animals; Zebrafish; Disintegrins; Gonads; Sex Differentiation; Germ Cells; Metalloproteases
PubMed: 36191636
DOI: 10.1016/j.ygcen.2022.114137 -
Journal of Microencapsulation Aug 2017Tumour poses tremendous challenges to mankind. In various tumours, matrix metalloproteases (MMPs) are ubiquitously over expressed and participate throughout the process... (Review)
Review
Tumour poses tremendous challenges to mankind. In various tumours, matrix metalloproteases (MMPs) are ubiquitously over expressed and participate throughout the process of tumour development. MMPs are commonly used as internal stimuli, and MMPs-responsive nanomaterials are classified into three categories according to the drug delivery process: administration and distribution to tumour, intratumoural distribution and cell internalisation, and specific drug release. First, MMPs-sensitive polyethylene glycol (PEG) de-shielding and activatable cell penetrating peptides were developed to improve the blood circulation time of drug delivery systems, thereby, enhancing tumour or stroma cells recognition and penetration. Following tumour recognition, the MMPs-sensitive and size- or morphology-changeable nanoparticles (NPs) could highly accumulate and penetrate into tumour. Lastly, several MMPs-sensitive drug release strategies were feasible for both small molecule drugs and macromolecule drugs. In conclusion, recent novel advances of MMPs-responsive nanomaterials in tumour targeting diagnosis and treatment were highlighted in this review.
Topics: Drug Delivery Systems; Humans; Matrix Metalloproteinases; Nanoparticles; Neoplasms
PubMed: 28617063
DOI: 10.1080/02652048.2017.1343873 -
Enzyme and Microbial Technology Jan 2023The rational design of enzymes with enhanced thermostability is efficient. Solvent-tolerant metalloprotease from Pseudomonas aeruginosa PT121 presents high Z-aspartame...
The rational design of enzymes with enhanced thermostability is efficient. Solvent-tolerant metalloprotease from Pseudomonas aeruginosa PT121 presents high Z-aspartame (Z-APM) synthesis activity, but insufficient thermostability. In this study, we enhanced enzyme thermostability using a rational strategy. Molecular dynamics (MD) simulation was applied to rapidly identify that the D28 and D116 mutations are likely to exhibit increased thermostability, and experimentation verified that the D28N and D116N mutants were more stable than the wild-type (WT) enzyme. In particular, the T of the D28N and D116N mutants increased by 6.1 °C and 9.2 °C, respectively, compared with that of the WT enzyme. The half-lives of D28N and D116N at 60 °C were 1.07- and 1.8-fold higher than that of the WT, respectively. Z-APM synthetic activities of the mutants were also improved. The potential mechanism of thermostability enhancement rationalized using MD simulation indicated that increased hydrogen bond interactions and a regional hydration shell were mostly responsible for the thermostability enhancement. Our strategy could be a reference for enzyme engineering, and our mutants offer considerable value in industrial applications.
Topics: Enzyme Stability; Temperature; Metalloproteases; Molecular Dynamics Simulation; Pseudomonas aeruginosa; Protein Engineering
PubMed: 36115275
DOI: 10.1016/j.enzmictec.2022.110123 -
Expert Review of Proteomics Dec 2018Metalloproteinases play key roles in health and disease, by generating novel proteoforms with variable structure and function. Areas covered: This review focuses on the... (Review)
Review
Metalloproteinases play key roles in health and disease, by generating novel proteoforms with variable structure and function. Areas covered: This review focuses on the role of endogenous [a Disintegrin and Metalloproteinase (ADAMs), ADAMs with thrombospondin motifs (ADAMTS), and matrix metalloproteinases (MMPs)] and exogenous metalloproteinases in various disease conditions, and describes the application of mass spectrometry-based proteomics to detect qualitative and quantitative changes in protein profiles in tissues and body fluids in disease. Emphasis is placed on the proteomic analysis of exudates collected from affected tissues, including methods that enrich newly generated protein fragments derived from proteolysis in cells, stroma, or extracellular matrix. The use of proteomic analysis of exudates in the study of the local tissue damage induced by metalloproteinases derived from viperid snake venoms is discussed, particularly in relation to extracellular matrix degradation and to the overall pathology of these envenomings. Expert commentary: The information provided by these proteomics approaches is paving the way for the identification of biomarkers based on particular proteolytic signatures associated with different pathologies. Together with other methodological approaches, a comprehensive view of the mechanisms and dynamics of diseases can be achieved. Such basis of knowledge allows for the design of novel diagnostic and therapeutic approaches within the frame of 'precision' or 'personalized' medicine.
Topics: Biomarkers; Exudates and Transudates; Humans; Metalloproteases; Molecular Diagnostic Techniques; Proteomics; Snake Bites
PubMed: 30348024
DOI: 10.1080/14789450.2018.1538800 -
Trends in Biochemical Sciences Apr 2018Limited proteolytic processing is an essential and ubiquitous post-translational modification (PTM) affecting secreted proteins; failure to regulate the process is often... (Review)
Review
Limited proteolytic processing is an essential and ubiquitous post-translational modification (PTM) affecting secreted proteins; failure to regulate the process is often associated with disease. Glycosylation is also a ubiquitous protein PTM and site-specific O-glycosylation in close proximity to sites of proteolysis can regulate and direct the activity of proprotein convertases, a disintegrin and metalloproteinases (ADAMs), and metalloproteinases affecting the activation or inactivation of many classes of proteins, including G-protein-coupled receptors (GPCRs). Here, we summarize the emerging data that suggest O-glycosylation to be a key regulator of limited proteolysis, and highlight the potential for crosstalk between multiple PTMs.
Topics: Animals; Disintegrins; Glycosylation; Humans; Metalloproteases; Protein Processing, Post-Translational; Proteolysis
PubMed: 29506880
DOI: 10.1016/j.tibs.2018.02.005