scholarly journals Cysteine Cathepsin Activity Regulation by Glycosaminoglycans

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Marko Novinec ◽  
Brigita Lenarčič ◽  
Boris Turk
Keyword(s):  
Antigen Processing ◽  
Critical Role ◽  
Cathepsin K ◽  
Extracellular Proteins ◽  
Collagenolytic Activity ◽  
Extracellular Milieu ◽  
Cysteine Cathepsins ◽  
Cathepsin Activity ◽  
Cysteine Cathepsin ◽  
Antigen Processing And Presentation

Cysteine cathepsins are a group of enzymes normally found in the endolysosomes where they are primarily involved in intracellular protein turnover but also have a critical role in MHC II-mediated antigen processing and presentation. However, in a number of pathologies cysteine cathepsins were found to be heavily upregulated and secreted into extracellular milieu, where they were found to degrade a number of extracellular proteins. A major role in modulating cathepsin activities play glycosaminoglycans, which were found not only to facilitate their autocatalytic activation including at neutral pH, but also to critically modulate their activities such as in the case of the collagenolytic activity of cathepsin K. The interaction between cathepsins and glycosaminoglycans will be discussed in more detail.

scholarly journals Cysteine Cathepsins and Their Prognostic and Therapeutic Relevance in Leukemia

2021 ◽  
Author(s):  
Mohit Arora ◽  
Garima Pandey ◽  
Shyam S. Chauhan
Keyword(s):  
Antigen Processing ◽  
Hematological Malignancies ◽  
Expression Patterns ◽  
Aberrant Expression ◽  
Hematopoietic Stem ◽  
Cysteine Cathepsins ◽  
Expression Activity ◽  
Available Information ◽  
Antigen Processing And Presentation ◽  
Selection Of

AbstractCysteine cathepsins are lysosomal proteases that require Cys-His ion pair in their catalytic site for enzymatic activity. While their aberrant expression and oncogenic functions have been widely reported in solid tumors, recent findings suggest that these proteases also play an important role in the pathogenesis of hematological malignancies. In this review, we summarize the potential clinical implications of cysteine cathepsins as diagnostic and prognostic markers in leukemia, and present evidences which supports the utility of these proteases as potential therapeutic targets in hematological malignancies. We also highlight the available information on the expression patterns, regulation, and potential functions of cysteine cathepsins in normal hematopoiesis and hematological malignancies. In hematopoiesis, cysteine cathepsins play a variety of physiological roles including regulation of hematopoietic stem cell adhesion in the bone marrow, trafficking, and maturation. They are also involved in several functions of immune cells which include the selection of lymphocytes in the thymus, antigen processing, and presentation. However, the expression of cysteine cathepsins is dysregulated in hematological malignancies where they have been shown to play diverse functions. Interestingly, several pieces of evidence over the past few years have demonstrated overexpression of cathepsins in leukemia and their association with worst survival outcomes in patients. Strategies aimed at altering the expression, activity, and subcellular localization of these cathepsins are emerging as potential therapeutic modalaties in the management of hematological malignancies. Recent findings also suggest the involvement of these proteases in modulating the immune response in leukemia and lymphomas.

scholarly journals The role of lysosomal enzymes in killing of mammalian cells by the lysosomotropic detergent N-dodecylimidazole.

1987 ◽  
Vol 104 (5) ◽  
pp. 1223-1229 ◽  
Author(s):  
P D Wilson ◽  
R A Firestone ◽  
J Lenard
Keyword(s):  
Cell Viability ◽  
Ammonium Chloride ◽  
Lysosomal Enzyme ◽  
Lysosomal Enzymes ◽  
Human Fibroblasts ◽  
Cysteine Proteases ◽  
Cytotoxic Agents ◽  
Cysteine Cathepsins ◽  
Cathepsin Activity ◽  
Cysteine Cathepsin

The sensitivity of cultured human and hamster fibroblast cells to killing by the lysosomotropic detergent N-dodecylimidazole (C12-Im) was investigated as a function of cellular levels of general lysosomal hydrolase activity, and specifically of cysteine cathepsin activity. Fibroblasts from patients with mucolipidosis II (I-cell disease) lack mannose-6-phosphate-containing proteins, and therefore possess only 10-15% of the normal level of most lysosomal hydrolases. I-cell fibroblasts are about one-half as sensitive to killing by C12-Im as are normal human fibroblasts. Overall lysosomal enzyme levels of CHO cells were experimentally manipulated in several ways without affecting cell viability: Growth in the presence of 10 mM ammonium chloride resulted in a gradual decrease in lysosomal enzyme content to 10-20% of control values within 3 d. Subsequent removal of ammonium chloride from the growth medium resulted in an increase in lysosomal enzymes, to approximately 125% of control values within 24 h. Treatment with 80 mM sucrose caused extensive vacuolization within 2 h; lysosomal enzyme levels remained at control levels for at least 6 h, but increased 15-fold after 24 h of treatment. Treatment with concanavalin A (50 micrograms/ml) also caused rapid (within 2 h) vacuolation with a sevenfold rise in lysosomal enzyme levels occurring only after 24 h. The sensitivity of these experimentally manipulated cells to killing by C12-Im always paralleled the measured intracellular lysosomal enzyme levels: lower levels were associated with decreased sensitivity while higher levels were associated with increased sensitivity, regardless of the degree of vacuolization of the cells. The cytotoxicity of the cysteine proteases (chiefly cathepsin L in our cells) was tested by inactivating them with the irreversible inhibitor E-64 (100 micrograms/ml). Cell viability, protein levels, and other lysosomal enzymes were unaffected, but cysteine cathepsin activity was reduced to less than 20% of control values. E-64-treated cells were almost completely resistant to C12-Im treatment, although lysosomal disruption appeared normal by fluorescent visualization of Lucifer Yellow CH-loaded cells. It is concluded that cysteine cathepsins are the major or sole cytotoxic agents released from lysosomes by C12-Im. These observations also confirm the previous conclusions that C12-Im kills cells as a consequence of lysosomal disruption.

scholarly journals After one year of the COVID-19 pandemic and hundreds of suggested drugs, will cathepsin L inhibitors be the solution?

Avicenna ◽  
2021 ◽  
Vol 2022 (1) ◽  
Author(s):  
Amr Ahmed ◽  
Mohammad Nezami ◽  
Abdullah Alkattan ◽  
Ahmed Mohamed ◽  
Omar Alshazly ◽  
...  
Keyword(s):  
Active Sites ◽  
Viral Infections ◽  
Cathepsin L ◽  
Docking Studies ◽  
Host Cells ◽  
Endosomal Membrane ◽  
Cysteine Cathepsins ◽  
Cathepsin Activity ◽  
Cysteine Cathepsin ◽  
One Year

Cysteine cathepsins are defined as lysosomal enzymes that are members of the papain family. Cysteine cathepsins (Cts) prevalently exist in whole organisms, varying from prokaryotes to mammals, and possess greatly conserved cysteine residues in their active sites. Cts are engaged in the digestion of cellular proteins, activation of zymogens, and remodeling of the extracellular matrix (ECM). Host cells are entered by SARS-CoV-2 via endocytosis. Cathepsin L and phosphatidylinositol 3-phosphate 5-kinase are crucial in endocytosis by cleaving the spike protein, which permits viral membrane fusion with the endosomal membrane and succeeds in the release of the viral genome to the host cell. Therefore, inhibition of cathepsin L may be advantageous in terms of decreasing infection caused by SARS-CoV-2. Coordinate inhibition of multiple Cts and lysosomal function by different drugs and biological agents might be of value for some purposes, such as a parasite or viral infections and antineoplastic applications. Zn2+ deficiency or dysregulation leads to exaggerated cysteine cathepsin activity, increasing the autoimmune/inflammatory response. For this purpose, Zn2+ metal can be safely combined with a drug that increases the anti-proteolytic effect of endogenous Zn2+, lowering the excessive activity of some CysCts. Biguanide derivative complexes with Zn2+ have been found to be promising inhibitors of CysCts protease reactions. Molecular docking studies of cathepsin L inhibited by the metformin-Zn+2 complex have been performed, showing two strong key interactions (Cys-25&His-163) and an extra H-bond with Asp-163 compared to cocrystallized Zn+2 (PDB ID 4axl).

scholarly journals C-terminal α-synuclein truncations are linked to cysteine cathepsin activity in Parkinson's disease

2019 ◽  
Vol 294 (25) ◽  
pp. 9973-9984 ◽  
Author(s):  
Ryan P. McGlinchey ◽  
Shannon M. Lacy ◽  
Katherine E. Huffer ◽  
Nahid Tayebi ◽  
Ellen Sidransky ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Amino Acids ◽  
Parkinson's Disease ◽  
Amyloid Fibrils ◽  
Lewy Bodies ◽  
Amyloid Formation ◽  
Pathological Feature ◽  
Cysteine Cathepsins ◽  
Cathepsin Activity ◽  
Cysteine Cathepsin

A pathological feature of Parkinson's disease (PD) is Lewy bodies (LBs) composed of α-synuclein (α-syn) amyloid fibrils. α-Syn is a 140 amino acids–long protein, but truncated α-syn is enriched in LBs. The proteolytic processes that generate these truncations are not well-understood. On the basis of our previous work, we propose that these truncations could originate from lysosomal activity attributable to cysteine cathepsins (Cts). Here, using a transgenic SNCAA53T mouse model, overexpressing the PD-associated α-syn variant A53T, we compared levels of α-syn species in purified brain lysosomes from nonsymptomatic mice with those in age-matched symptomatic mice. In the symptomatic mice, antibody epitope mapping revealed enrichment of C-terminal truncations, resulting from CtsB, CtsL, and asparagine endopeptidase. We did not observe changes in individual cathepsin activities, suggesting that the increased levels of C-terminal α-syn truncations are because of the burden of aggregated α-syn. Using LC-MS and purified α-syn, we identified C-terminal truncations corresponding to amino acids 1–122 and 1–90 from the SNCAA53T lysosomes. Feeding rat dopaminergic N27 cells with exogenous α-syn fibrils confirmed that these fragments originate from incomplete fibril degradation in lysosomes. We mimicked these events in situ by asparagine endopeptidase degradation of α-syn fibrils. Importantly, the resulting C-terminally truncated fibrils acted as superior seeds in stimulating α-syn aggregation compared with that of the full-length fibrils. These results unequivocally show that C-terminal α-syn truncations in LBs are linked to Cts activities, promote amyloid formation, and contribute to PD pathogenesis.

scholarly journals Cystatins, cysteine peptidase inhibitors, as regulators of immune cell cytotoxicity

2017 ◽  
Vol 118 (4) ◽  
Author(s):  
Mateja Prunk ◽  
Milica Perišić Nanut ◽  
Jerica Sabotič ◽  
Janko Kos
Keyword(s):  
Immune Response ◽  
Nk Cells ◽  
Antigen Processing ◽  
Immune Cell ◽  
Cell Cytotoxicity ◽  
Inhibitory Function ◽  
Cysteine Cathepsins ◽  
Living Organisms ◽  
Main Regulator ◽  
Antigen Processing And Presentation

Cystatins comprise a superfamily of evolutionarily related proteins, present in all living organisms, from protozoa to mammals. They act as inhibitors of cysteine peptidases although they can also function independently of their inhibitory function. Cysteine cathepsins are implicated in various physiological and pathological processes. In the immune response they are involved in antigen processing and presentation, the cytotoxicity of natural killer (NK) cells and cytotoxic T lymphocytes (CTL), migration and adhesion of immune cells, cytokine and growth factor regulation and toll-like receptor signalling. Cystatins are probably involved in the regulation of all these processes; importantly, cystatin F has a crucial role in the regulation of immune cell cytotoxicity. NK cells and CTLs exploit the granzyme/perforin pathway for target cell killing, with perforin and granzymes as crucial effector molecules. Granzymes are synthesized as inactive pro-granzymes and need to be proteolytically activated by cathepsins C and H. Cystatin F is the main regulator of the activity of cathepsins C and H in cytotoxic cells and, consequently, regulates their cytotoxicity. The role of cystatins and cysteine cathepsins in the immune response is presented, with emphasis on their role in the regulation of cytotoxicity of NK cells and CTLs.

scholarly journals Mannose 6 phosphorylation of lysosomal enzymes controls B cell functions

2015 ◽  
Vol 208 (2) ◽  
pp. 171-180 ◽  
Author(s):  
Takanobu Otomo ◽  
Michaela Schweizer ◽  
Katrin Kollmann ◽  
Valéa Schumacher ◽  
Nicole Muschol ◽  
...  
Keyword(s):  
B Cell ◽  
Antigen Processing ◽  
Lysosomal Enzymes ◽  
Intracellular Transport ◽  
Critical Role ◽  
Significant Loss ◽  
Cell Functions ◽  
Dependent Transport ◽  
Antigen Processing And Presentation

Antigen processing and presentation and cytotoxic targeting depend on the activities of several lysosomal enzymes that require mannose 6-phosphate (M6P) sorting signals for efficient intracellular transport and localization. In this paper, we show that mice deficient in the formation of M6P residues exhibit significant loss of cathepsin proteases in B cells, leading to lysosomal dysfunction with accumulation of storage material, impaired antigen processing and presentation, and subsequent defects in B cell maturation and antibody production. The targeting of lysosomal and granular enzymes lacking M6P residues is less affected in dendritic cells and T cells and sufficient for maintenance of degradative and lytic functions. M6P deficiency also impairs serum immunoglobulin levels and antibody responses to vaccination in patients. Our data demonstrate the critical role of M6P-dependent transport routes for B cell functions in vivo and humoral immunity in mice and human.

scholarly journals Cancer Stem Cells Are Possible Key Players in Regulating Anti-Tumor Immune Responses: The Role of Immunomodulating Molecules and MicroRNAs

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1674
Author(s):  
Sara Tomei ◽  
Ola Ibnaof ◽  
Shilpa Ravindran ◽  
Soldano Ferrone ◽  
Cristina Maccalli
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Immune Responses ◽  
Antigen Processing ◽  
Aberrant Expression ◽  
Immunological Profile ◽  
Malignant Lesions ◽  
Novel Therapeutic Strategies ◽  
Antigen Processing And Presentation

Cancer cells endowed with stemness properties and representing a rare population of cells within malignant lesions have been isolated from tumors with different histological origins. These cells, denominated as cancer stem cells (CSCs) or cancer initiating cells (CICs), are responsible for tumor initiation, progression and resistance to therapies, including immunotherapy. The dynamic crosstalk of CSCs/CICs with the tumor microenvironment orchestrates their fate and plasticity as well as their immunogenicity. CSCs/CICs, as observed in multiple studies, display either the aberrant expression of immunomodulatory molecules or suboptimal levels of molecules involved in antigen processing and presentation, leading to immune evasion. MicroRNAs (miRNAs) that can regulate either stemness properties or their immunological profile, with in some cases dual functions, can provide insights into these mechanisms and possible interventions to develop novel therapeutic strategies targeting CSCs/CICs and reverting their immunogenicity. In this review, we provide an overview of the immunoregulatory features of CSCs/CICs including miRNA profiles involved in the regulation of the interplay between stemness and immunological properties.

scholarly journals NK cell-based cancer immunotherapy: from basic biology to clinical development

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Sizhe Liu ◽  
Vasiliy Galat ◽  
Yekaterina Galat4 ◽  
Yoo Kyung Annie Lee ◽  
Derek Wainwright ◽  
...  
Keyword(s):  
Cancer Immunotherapy ◽  
T Cell Activation ◽  
Cell Biology ◽  
Antigen Processing ◽  
Cell Activation ◽  
Nk Cell ◽  
Critical Role ◽  
Clinical Development ◽  
Target Cells ◽  
Immune Effector

AbstractNatural killer (NK) cell is a specialized immune effector cell type that plays a critical role in immune activation against abnormal cells. Different from events required for T cell activation, NK cell activation is governed by the interaction of NK receptors with target cells, independent of antigen processing and presentation. Due to relatively unsophisticated cues for activation, NK cell has gained significant attention in the field of cancer immunotherapy. Many efforts are emerging for developing and engineering NK cell-based cancer immunotherapy. In this review, we provide our current understandings of NK cell biology, ongoing pre-clinical and clinical development of NK cell-based therapies and discuss the progress, challenges, and future perspectives.

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