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Communications Biology Oct 2023Lung cancer, a major contributor to cancer-related fatalities worldwide, involves a complex pathogenesis. Cathepsins, lysosomal cysteine proteases, play roles in various...
Lung cancer, a major contributor to cancer-related fatalities worldwide, involves a complex pathogenesis. Cathepsins, lysosomal cysteine proteases, play roles in various physiological and pathological processes, including tumorigenesis. Observational studies have suggested an association between cathepsins and lung cancer. However, the causal link between the cathepsin family and lung cancer remains undetermined. This study employed Mendelian randomization analyses to investigate this causal association. The univariable Mendelian randomization analysis results indicate that elevated cathepsin H levels increase the overall risk of lung cancer, adenocarcinoma, and lung cancer among smokers. Conversely, reverse Mendelian randomization analyses suggest that squamous carcinoma may lead to increased cathepsin B levels. A multivariable analysis using nine cathepsins as covariates reveals that elevated cathepsin H levels lead to an increased overall risk of lung cancer, adenocarcinoma, and lung cancer in smokers. In conclusion, cathepsin H may serve as a marker for lung cancer, potentially inspiring directions in lung cancer diagnosis and treatment.
Topics: Humans; Cathepsin H; Lung Neoplasms; Mendelian Randomization Analysis; Cathepsin L; Adenocarcinoma
PubMed: 37805623
DOI: 10.1038/s42003-023-05408-7 -
Cathepsin S (CTSS) activity in health and disease - A treasure trove of untapped clinical potential.Molecular Aspects of Medicine Dec 2022Amongst the lysosomal cysteine cathepsin family of proteases, cathepsin S (CTSS) holds particular interest due to distinctive properties including a normal restricted... (Review)
Review
Amongst the lysosomal cysteine cathepsin family of proteases, cathepsin S (CTSS) holds particular interest due to distinctive properties including a normal restricted expression profile, inducible upregulation and activity at a broad pH range. Consequently, while CTSS is well-established as a member of the proteolytic cocktail within the lysosome, degrading unwanted and damaged proteins, it has increasingly been shown to mediate a number of distinct, more selective roles including antigen processing and antigen presentation, and cleavage of substrates both intra and extracellularly. Increasingly, aberrant CTSS expression has been demonstrated in a variety of conditions and disease states, marking it out as both a biomarker and potential therapeutic target. This review seeks to contextualise CTSS within the cysteine cathepsin family before providing an overview of the broad range of pathologies in which roles for CTSS have been identified. Additionally, current clinical progress towards specific inhibitors is detailed, updating the position of the field in exploiting this most unique of proteases.
Topics: Humans; Cysteine; Cathepsins; Lysosomes; Proteolysis
PubMed: 35868042
DOI: 10.1016/j.mam.2022.101106 -
Biochimica Et Biophysica Acta. Proteins... Sep 2020Microglia, the resident mononuclear phagocyte population in the brain, have long been implicated in the pathology of neurodegenerative age-associated disorders. However,... (Review)
Review
Microglia, the resident mononuclear phagocyte population in the brain, have long been implicated in the pathology of neurodegenerative age-associated disorders. However, activated microglia have now been identified as homeostatic keepers in the brain, because they are involved in the initiation and resolution of neuropathology. The complex roles of activated microglia appear to be linked to change from inflammatory and neurotoxic to anti-inflammatory and neuroprotective phenotypes. Increased expression and secretion of various cathepsins support roles of activated microglia in chronic neuroinflammation, the neurotoxic M1-like polarization and neuronal death. Moreover, changes in expression and localization of microglial cathepsin B play a critical role in the acceleration of the brain aging. Beyond the role as brain-resident macrophages, many lines of evidence have shown that microglia have essential roles in the maturation and maintenance of neuronal circuits in the developing and adult brain. Cathepsin S secreted from microglia induces the diurnal variation of spine density of cortical neurons though proteolytic modification of peri-synaptic extracellular matrix molecules. In this review, I highlight the emerging roles of cathepsins that support the roles of microglia in both normal healthy and pathological brains. In addition, I discuss cathepsin inhibitors as potential therapeutic targets for brain disorders.
Topics: Animals; Brain; Cathepsin B; Cathepsin H; Cathepsins; Chronic Pain; Humans; Inflammation; Microglia; NLR Family, Pyrin Domain-Containing 3 Protein; Neurodegenerative Diseases; Neurons; Phenotype
PubMed: 32526473
DOI: 10.1016/j.bbapap.2020.140465 -
Biochimica Et Biophysica Acta. Proteins... Apr 2020Cysteinyl cathepsins are lysosomal/endosomal proteases that mediate bulk protein degradation in these intracellular acidic compartments. Yet, studies indicate that these... (Review)
Review
Cysteinyl cathepsins are lysosomal/endosomal proteases that mediate bulk protein degradation in these intracellular acidic compartments. Yet, studies indicate that these proteases also appear in the nucleus, nuclear membrane, cytosol, plasma membrane, and extracellular space. Patients with cardiovascular diseases (CVD) show increased levels of cathepsins in the heart, aorta, and plasma. Plasma cathepsins often serve as biomarkers or risk factors of CVD. In aortic diseases, such as atherosclerosis and abdominal aneurysms, cathepsins play pathogenic roles, but many of the same cathepsins are cardioprotective in hypertensive, hypertrophic, and infarcted hearts. During the development of CVD, cathepsins are regulated by inflammatory cytokines, growth factors, hypertensive stimuli, oxidative stress, and many others. Cathepsin activities in inflammatory molecule activation, immunity, cell migration, cholesterol metabolism, neovascularization, cell death, cell signaling, and tissue fibrosis all contribute to CVD and are reviewed in this article in memory of Dr. Nobuhiko Katunuma for his contribution to the field.
Topics: Animals; Aortic Aneurysm, Abdominal; Atherosclerosis; Biomarkers; Cardiovascular Diseases; Cathepsins; Humans; Mice; Risk Factors
PubMed: 31926332
DOI: 10.1016/j.bbapap.2020.140360 -
Organic & Biomolecular Chemistry Jul 2021Cysteine cathepsins are proteases critical in physiopathological processes and show potential as targets or biomarkers for diseases and medical conditions. The 11... (Review)
Review
Cysteine cathepsins are proteases critical in physiopathological processes and show potential as targets or biomarkers for diseases and medical conditions. The 11 members of the cathepsin family are redundant in some cases but remarkably independent of others, demanding the development of both pan-cathepsin targeting tools as well as probes that are selective for specific cathepsins with little off-target activity. This review addresses the diverse design strategies that have been employed to accomplish this tailored selectivity among cysteine cathepsin targets and the imaging modalities incorporated. The power of these diverse tools is contextualized by briefly highlighting the nature of a few prominent cysteine cathepsins, their involvement in select diseases, and the application of cathepsin imaging probes in research spanning basic biochemical studies to clinical applications.
Topics: Cathepsins
PubMed: 34288999
DOI: 10.1039/d1ob00225b -
International Journal of Molecular... Aug 2022Cathepsins encompass a family of lysosomal proteases that mediate protein degradation and turnover. Although mainly localized in the endolysosomal compartment,... (Review)
Review
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.
Topics: Cathepsins; Endopeptidases; Humans; Lysosomes; Peptide Hydrolases; Virus Diseases
PubMed: 36012353
DOI: 10.3390/ijms23169089 -
Biochemistry Sep 2022Cathepsin B is a lysosomal protease that participates in protein degradation. However, cathepsin B is also active under neutral pH conditions of the cytosol, nuclei, and...
Cathepsin B is a lysosomal protease that participates in protein degradation. However, cathepsin B is also active under neutral pH conditions of the cytosol, nuclei, and extracellular locations. The dipeptidyl carboxypeptidase (DPCP) activity of cathepsin B, assayed with the Abz-GIVR↓AK(Dnp)-OH substrate, has been reported to display an acidic pH optimum. In contrast, the endopeptidase activity, monitored with Z-RR-↓AMC, has a neutral pH optimum. These observations raise the question of whether other substrates can demonstrate cathepsin B DPCP activity at neutral pH and endopeptidase activity at acidic pH. To address this question, global cleavage profiling of cathepsin B with a diverse peptide library was conducted under acidic and neutral pH conditions. Results revealed that cathepsin B has (1) major DPCP activity and modest endopeptidase activity under both acidic and neutral pH conditions and (2) distinct pH-dependent amino acid preferences adjacent to cleavage sites for both DPCP and endopeptidase activities. The pH-dependent cleavage preferences were utilized to design a new Abz-GVR↓AK(Dnp)-OH DPCP substrate, with norleucine (n) at the P3 position, having improved DPCP activity of cathepsin B at neutral pH compared to the original Abz-GIVR↓AK(Dnp)-OH substrate. The new Z-VR-AMC and Z-ER-AMC substrates displayed improved endopeptidase activity at acidic pH compared to the original Z-RR-AMC. These findings illustrate the new concept that cathepsin B possesses DPCP and endopeptidase activities at both acidic and neutral pH values. These results advance understanding of the pH-dependent cleavage properties of the dual DPCP and endopeptidase activities of cathepsin B that function under different cellular pH conditions.
Topics: Cathepsin B; Cathepsins; Endopeptidases; Hydrogen-Ion Concentration; Hydrolysis; Proteolysis; Substrate Specificity
PubMed: 35981509
DOI: 10.1021/acs.biochem.2c00358 -
Advances in Experimental Medicine and... 2011Cysteine proteases are important for the growth and survival of apicomplexan parasites that infect humans. The apicomplexan Toxoplasma gondii expresses five members of... (Review)
Review
Cysteine proteases are important for the growth and survival of apicomplexan parasites that infect humans. The apicomplexan Toxoplasma gondii expresses five members of the C1 family of cysteine proteases, including one cathepsin L-like (TgCPL), one cathepsin B-like (TgCPB) and three cathepsin C-like (TgCPC1, 2 and 3) proteases. Recent genetic, biochemical and structural studies reveal that cathepsins function in microneme and rhoptry protein maturation, host cell invasion, replication and nutrient acquisition. here, we review the key features and roles of T. gondii cathepsins and discuss the therapeutic potential for specific inhibitor development.
Topics: Amino Acid Sequence; Cathepsins; Humans; Molecular Sequence Data; Phylogeny; Protein Transport; Toxoplasma
PubMed: 21660658
DOI: 10.1007/978-1-4419-8414-2_4 -
The Biochemical Journal Nov 1980Cathepsin H was purified from human liver by a method involving autolysis and acetone fractionation, and chromatography on DEAE-cellulose, Ultrogel AcA 54,...
Cathepsin H was purified from human liver by a method involving autolysis and acetone fractionation, and chromatography on DEAE-cellulose, Ultrogel AcA 54, hydroxyapatite and concanavalin A-Sepharose. The procedure allowed for the simultaneous isolation of cathepsin B and cathepsin D. Cathepsin H was shown to consist of a single polypeptide chain of 28 000 mol.wt., and affinity for concanavalin A-Sepharose indicated that it was a glycoprotein. The enzyme existed in multiple isoelectric forms, the two major forms having pI values of 6.0 and 6.4; it hydrolysed azocasein (pH optimum 5.5), benzoylarginine 2-naphthylamide (Ba-Arg-NNap), leucyl 2-naphthylamide (Arg-NNap), (pH optimum 6.8). Arg-NNap and Arg-NMec, unlike Bz-Arg-NNap-, were not hydrolysed by human cathepsin B. Cathepsin H was similar to cathepsin B in being irreversibly inactivated by exposure to alkaline pH. Sensitivity to chemical inhibitors by 1 microM-leupeptin, which gave essentially complete inhibition of the other lysosomal cysteine proteinases, cathepsins B and L.
Topics: Cathepsins; Chemical Phenomena; Chemistry; Chromatography, DEAE-Cellulose; Chromatography, Gel; Humans; Isoenzymes; Liver; Methods; Substrate Specificity; alpha-Macroglobulins
PubMed: 6165352
DOI: 10.1042/bj1910487 -
Biomedicine & Pharmacotherapy =... Jan 2022Cathepsin S (CTSS), a lysosomal protease, belongs to a family of cysteine cathepsin proteases that promote degradation of damaged proteins in the endolysosomal pathway.... (Review)
Review
Cathepsin S (CTSS), a lysosomal protease, belongs to a family of cysteine cathepsin proteases that promote degradation of damaged proteins in the endolysosomal pathway. Aberrant CTSS expression and regulation are associated with the pathogenesis of several diseases, including lung diseases. CTSS overexpression causes a variety of pathological processes, including pulmonary fibrosis, with increased CTSS secretion and accelerated extracellular matrix remodeling. Compared to many other cysteine cathepsin family members, CTSS has unique features that it presents limited tissue expression and retains its enzymatic activity at a neutral pH, suggesting its decisive involvement in disease microenvironments. In this review, we investigated the role of CTSS in lung disease, exploring recent studies that have indicated that CTSS mediates fibrosis in unique ways, along with its structure, substrates, and distinct regulation. We also outlined examples of CTSS inhibitors in clinical and preclinical development and proposed CTSS as a potential therapeutic target for pulmonary fibrosis.
Topics: Animals; Cathepsins; Drug Development; Extracellular Matrix; Humans; Hydrogen-Ion Concentration; Molecular Targeted Therapy; Pulmonary Fibrosis
PubMed: 34772578
DOI: 10.1016/j.biopha.2021.112245