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Article ; Online: γ-Enolase enhances Trk endosomal trafficking and promotes neurite outgrowth in differentiated SH-SY5Y cells.

Pišlar, Anja / Kos, Janko

2021 Volume 19, Issue 1, Page(s) 118

Abstract: Background: Neurotrophins can activate multiple signalling pathways in neuronal cells through binding to their cognate receptors, leading to neurotrophic processes such as cell survival and differentiation. γ-Enolase has been shown to have a ... ...

Abstract	Background: Neurotrophins can activate multiple signalling pathways in neuronal cells through binding to their cognate receptors, leading to neurotrophic processes such as cell survival and differentiation. γ-Enolase has been shown to have a neurotrophic activity that depends on its translocation towards the plasma membrane by the scaffold protein γ1-syntrophin. The association of γ-enolase with its membrane receptor or other binding partners at the plasma membrane remains unknown. Methods: In the present study, we used immunoprecipitation and immunofluorescence to show that γ-enolase associates with the intracellular domain of the tropomyosin receptor kinase (Trk) family of tyrosine kinase receptors at the plasma membrane of differentiated SH-SY5Y cells. Results: In differentiated SH-SY5Y cells with reduced expression of γ1-syntrophin, the association of γ-enolase with the Trk receptor was diminished due to impaired translocation of γ-enolase towards the plasma membrane or impaired Trk activity. Treatment of differentiated SH-SY5Y cells with a γ-Eno peptide that mimics γ-enolase neurotrophic activity promoted Trk receptor internalisation and endosomal trafficking, as defined by reduced levels of Trk in clathrin-coated vesicles and increased levels in late endosomes. In this way, γ-enolase triggers Rap1 activation, which is required for neurotrophic activity of γ-enolase. Additionally, the inhibition of Trk kinase activity by K252a revealed that increased SH-SY5Y cell survival and neurite outgrowth mediated by the γ-Eno peptide through activation of signalling cascade depends on Trk kinase activity. Conclusions: These data therefore establish the Trk receptor as a binding partner of γ-enolase, whereby Trk endosomal trafficking is promoted by γ-Eno peptide to mediate its neurotrophic signalling. Video abstract.
MeSH term(s)	Cell Differentiation ; Cell Line, Tumor ; Humans ; Neurites/physiology ; Phosphopyruvate Hydratase/metabolism ; Receptor, trkA/metabolism
Chemical Substances	Receptor, trkA (EC 2.7.10.1) ; Phosphopyruvate Hydratase (EC 4.2.1.11)
Language	English
Publishing date	2021-12-11
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2126315-2
ISSN	1478-811X ; 1478-811X
ISSN (online)	1478-811X
ISSN	1478-811X
DOI	10.1186/s12964-021-00784-1
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Article ; Online: γ-Enolase enhances Trk endosomal trafficking and promotes neurite outgrowth in differentiated SH-SY5Y cells

Anja Pišlar / Janko Kos

Cell Communication and Signaling, Vol 19, Iss 1, Pp 1-

2021 Volume 18

Abstract: Abstract Background Neurotrophins can activate multiple signalling pathways in neuronal cells through binding to their cognate receptors, leading to neurotrophic processes such as cell survival and differentiation. γ-Enolase has been shown to have a ... ...

Abstract	Abstract Background Neurotrophins can activate multiple signalling pathways in neuronal cells through binding to their cognate receptors, leading to neurotrophic processes such as cell survival and differentiation. γ-Enolase has been shown to have a neurotrophic activity that depends on its translocation towards the plasma membrane by the scaffold protein γ1-syntrophin. The association of γ-enolase with its membrane receptor or other binding partners at the plasma membrane remains unknown. Methods In the present study, we used immunoprecipitation and immunofluorescence to show that γ-enolase associates with the intracellular domain of the tropomyosin receptor kinase (Trk) family of tyrosine kinase receptors at the plasma membrane of differentiated SH-SY5Y cells. Results In differentiated SH-SY5Y cells with reduced expression of γ1-syntrophin, the association of γ-enolase with the Trk receptor was diminished due to impaired translocation of γ-enolase towards the plasma membrane or impaired Trk activity. Treatment of differentiated SH-SY5Y cells with a γ-Eno peptide that mimics γ-enolase neurotrophic activity promoted Trk receptor internalisation and endosomal trafficking, as defined by reduced levels of Trk in clathrin-coated vesicles and increased levels in late endosomes. In this way, γ-enolase triggers Rap1 activation, which is required for neurotrophic activity of γ-enolase. Additionally, the inhibition of Trk kinase activity by K252a revealed that increased SH-SY5Y cell survival and neurite outgrowth mediated by the γ-Eno peptide through activation of signalling cascade depends on Trk kinase activity. Conclusions These data therefore establish the Trk receptor as a binding partner of γ-enolase, whereby Trk endosomal trafficking is promoted by γ-Eno peptide to mediate its neurotrophic signalling. Graphical Abstract Video abstract
Keywords	γ-Enolase ; Trk receptor ; Clathrin-mediated endocytosis ; Late endosomes ; Neurite outgrowth ; Medicine ; R ; Cytology ; QH573-671
Subject code	571
Language	English
Publishing date	2021-12-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
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Article ; Online: New Insights into the Role of Cysteine Cathepsins in Neuroinflammation.

Pišlar, Anja / Bolčina, Lara / Kos, Janko

Biomolecules

2021 Volume 11, Issue 12

Abstract: Neuroinflammation, which is mediated by microglia and astrocytes, is associated with the progression of neurodegenerative diseases. Increasing evidence shows that activated microglia induce the expression and secretion of various lysosomal cathepsins, ... ...

Abstract	Neuroinflammation, which is mediated by microglia and astrocytes, is associated with the progression of neurodegenerative diseases. Increasing evidence shows that activated microglia induce the expression and secretion of various lysosomal cathepsins, particularly during the early stage of neuroinflammation. This trigger signaling cascade that aggravate neurodegeneration. To date, most research on neuroinflammation has focused on the role of cysteine cathepsins, the largest cathepsin family. Cysteine cathepsins are primarily responsible for protein degradation in lysosomes; however, they also play a role in regulating a number of other important physiological and pathological processes. This review focuses on the functional roles of cysteine cathepsins in the central nervous system during neuroinflammation, with an emphasis on their roles in the polarization of microglia and neuroinflammation signaling, which in turn causes neuronal death and thus neurodegeneration.
MeSH term(s)	Cysteine Proteases/metabolism ; Disease Progression ; Gene Expression Regulation ; Humans ; Lysosomes/metabolism ; Microglia/metabolism ; Microglia/physiology ; Neuroinflammatory Diseases/metabolism ; Neuroinflammatory Diseases/physiopathology ; Proteolysis
Chemical Substances	Cysteine Proteases (EC 3.4.-)
Language	English
Publishing date	2021-11-30
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2701262-1
ISSN	2218-273X ; 2218-273X
ISSN (online)	2218-273X
ISSN	2218-273X
DOI	10.3390/biom11121796
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Article ; Online: Cell models for Alzheimer's and Parkinson's disease: At the interface of biology and drug discovery.

Cetin, Sandra / Knez, Damijan / Gobec, Stanislav / Kos, Janko / Pišlar, Anja

Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie

2022 Volume 149, Page(s) 112924

Abstract: Neurodegenerative diseases are severely debilitating conditions characterized primarily by progressive neuronal loss and impairment of the nervous system. Alzheimer's and Parkinson's diseases are the most common neurodegenerative disorders, and their ... ...

Abstract	Neurodegenerative diseases are severely debilitating conditions characterized primarily by progressive neuronal loss and impairment of the nervous system. Alzheimer's and Parkinson's diseases are the most common neurodegenerative disorders, and their impact is increasing as average life expectancy increases worldwide. Although the underlying mechanisms of both progressive diseases have been extensively studied, we still lack a comprehensive understanding of the molecular basis of both diseases. Current therapeutic options do not slow the progression of the diseases and only provide symptom relief. Cell models that resemble the characteristics of the disease in question are important in drug discovery projects because they provide information about the therapeutic benefits of drugs under development. Here, we review current in vitro cell models used to study the molecular basis of Alzheimer's and Parkinson's disease focusing on their potential for discovering of disease-modifying therapeutics to combat neurodegenerative diseases. We discuss phenotypic screening as an important approach for identifying novel therapeutic molecules. Advances in the development of cell-based assays for drug discovery are discussed, ranging from simple monoculture cell models to high-throughput three-dimensional cell models. Finally, we critically present the limitations of cell models and the caveats encountered in drug discovery to find effective treatment for neurodegenerative diseases.
MeSH term(s)	Alzheimer Disease/drug therapy ; Biology ; Drug Discovery ; Humans ; Neurodegenerative Diseases/drug therapy ; Parkinson Disease/drug therapy
Language	English
Publishing date	2022-04-08
Publishing country	France
Document type	Journal Article ; Review
ZDB-ID	392415-4
ISSN	1950-6007 ; 0753-3322 ; 0300-0893
ISSN (online)	1950-6007
ISSN	0753-3322 ; 0300-0893
DOI	10.1016/j.biopha.2022.112924
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Article ; Online: Lysosomal peptidases-intriguing roles in cancer progression and neurodegeneration.

Kos, Janko / Mitrović, Ana / Perišić Nanut, Milica / Pišlar, Anja

FEBS open bio

2022 Volume 12, Issue 4, Page(s) 708–738

Abstract: Lysosomal peptidases are hydrolytic enzymes capable of digesting waste proteins that are targeted to lysosomes via endocytosis and autophagy. Besides intracellular protein catabolism, they play more specific roles in several other cellular processes and ... ...

Abstract	Lysosomal peptidases are hydrolytic enzymes capable of digesting waste proteins that are targeted to lysosomes via endocytosis and autophagy. Besides intracellular protein catabolism, they play more specific roles in several other cellular processes and pathologies, either within lysosomes, upon secretion into the cell cytoplasm or extracellular space, or bound to the plasma membrane. In cancer, lysosomal peptidases are generally associated with disease progression, as they participate in crucial processes leading to changes in cell morphology, signaling, migration, and invasion, and finally metastasis. However, they can also enhance the mechanisms resulting in cancer regression, such as apoptosis of tumor cells or antitumor immune responses. Lysosomal peptidases have also been identified as hallmarks of aging and neurodegeneration, playing roles in oxidative stress, mitochondrial dysfunction, abnormal intercellular communication, dysregulated trafficking, and the deposition of protein aggregates in neuronal cells. Furthermore, deficiencies in lysosomal peptidases may result in other pathological states, such as lysosomal storage disease. The aim of this review was to highlight the role of lysosomal peptidases in particular pathological processes of cancer and neurodegeneration and to address the potential of lysosomal peptidases in diagnosing and treating patients.
MeSH term(s)	Apoptosis/physiology ; Humans ; Lysosomes/metabolism ; Neoplasms ; Neoplastic Processes ; Peptide Hydrolases/metabolism
Chemical Substances	Peptide Hydrolases (EC 3.4.-)
Language	English
Publishing date	2022-02-03
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2651702-4
ISSN	2211-5463 ; 2211-5463
ISSN (online)	2211-5463
ISSN	2211-5463
DOI	10.1002/2211-5463.13372
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Article: Myeloid-Derived Suppressor Cells Hamper Natural Killer Cell Activity in Cancer: Role of Peptidases.

Jakoš, Tanja / Pišlar, Anja / Jewett, Anahid / Kos, Janko

Critical reviews in immunology

2021 Volume 41, Issue 2, Page(s) 77–99

Abstract: Natural killer (NK) cells represent critical effectors of anti-tumor immune responses due to their ability to target tumor cells that escape recognition by the adaptive arm of the immune system. NK cell efficacy depends on multiple factors, including ... ...

Abstract	Natural killer (NK) cells represent critical effectors of anti-tumor immune responses due to their ability to target tumor cells that escape recognition by the adaptive arm of the immune system. NK cell efficacy depends on multiple factors, including their propensity to infiltrate tumors, to reach activation threshold, and to differentiate into mature cytotoxic cells. The tumor microenvironment counteracts protective immunity by delivering anti-inflammatory signals, which stimulate the development of myeloid-derived suppressor cells (MDSC). MDSCs utilize numerous proximity-dependent and independent mechanisms to suppress functions of cytotoxic T lymphocytes and NK cells. Importantly, substantial part of their suppressive activity depends on peptidases. MDSC-derived peptidases incapacitate NK cells by shedding ligands for their activating receptors and by processing key cytokines involved in regulation of immune responses. Moreover, they are needed for sustaining the immunosuppressive loop through promotion of MDSC accumulation, expansion, and enhancement of their survival. Peptidases are at the forefront of cancer progression. However, their disparate roles in immune cells have only recently become appreciated in orchestration of the cancer immune responses. Studies that focused on elucidating the potential of peptidase inhibitors in regulation of the anti-tumor immune responses have led to renewed interest in clinical development of peptidase inhibitors. In parallel, they inspired the development of novel theranostics, that exploit increased activity of peptidases in infiltrating immune cells for targeted drug release or activation of imaging probes.
MeSH term(s)	Humans ; Killer Cells, Natural ; Myeloid-Derived Suppressor Cells ; Neoplasms/therapy ; Peptide Hydrolases ; Tumor Microenvironment
Chemical Substances	Peptide Hydrolases (EC 3.4.-)
Language	English
Publishing date	2021-08-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	1353116-5
ISSN	1040-8401
ISSN	1040-8401
DOI	10.1615/CritRevImmunol.2021037197
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Article ; Online: Cathepsin X Activity Does Not Affect NK-Target Cell Synapse but Is Rather Distributed to Cytotoxic Granules.

Jakoš, Tanja / Prunk, Mateja / Pišlar, Anja / Kos, Janko

International journal of molecular sciences

2021 Volume 22, Issue 24

Abstract: Cathepsin X is a lysosomal peptidase that is involved in tumour progression and represents a potential target for therapeutic interventions. In addition, it regulates important functions of immune cells and is implicated in the modulation of tumour cell- ... ...

Abstract	Cathepsin X is a lysosomal peptidase that is involved in tumour progression and represents a potential target for therapeutic interventions. In addition, it regulates important functions of immune cells and is implicated in the modulation of tumour cell-immune cell crosstalk. Selective cathepsin X inhibitors have been proposed as prospective antitumour agents to prevent cancer progression; however, their impact on the antitumour immune response has been overlooked. Previous studies indicate that the migration and adhesion of T cells and dendritic cells are affected by diminished cathepsin X activity. Meanwhile, the influence of cathepsin X inhibition on natural killer (NK) cell function has not yet been explored. Here, we examined the localization patterns of cathepsin X and the role of its inhibitors on the cytotoxicity of cell line NK-92, which is used for adoptive cellular immunotherapy in cancer patients. NK-92 cells depend on lymphocyte function-associated antigen 1 (LFA-1) to form stable immunoconjugates with target cells, providing, in this way, optimal cytotoxicity. Since LFA-1 is a substrate for cathepsin X activity in other types of cells, we hypothesized that cathepsin X could disturb the formation of NK-92 immunoconjugates. Thus, we employed cathepsin X reversible and irreversible inhibitors and evaluated their effects on the NK-92 cell interactions with target cells and on the NK-92 cell cytotoxicity. We show that cathepsin X inhibition does not impair stable conjugate formation or the lytic activity of NK-92 cells. Similarly, the conjugate formation between Jurkat T cells and target cells was not affected by cathepsin X activity. Unlike in previous migration and adhesion studies on T cells, in NK-92 cells cathepsin X was not co-localized with LFA-1 at the plasma membrane but was, rather, redistributed to the cytotoxic granules and secreted during degranulation.
MeSH term(s)	Antineoplastic Agents/pharmacology ; Cathepsins/pharmacology ; Cell Line, Tumor ; Cell Membrane/drug effects ; Cytoplasmic Granules/drug effects ; Cytotoxicity, Immunologic/drug effects ; Humans ; Immunotherapy, Adoptive/methods ; Jurkat Cells ; K562 Cells ; Killer Cells, Natural/drug effects ; Neoplasms/drug therapy ; Synapses/drug effects ; T-Lymphocytes/drug effects
Chemical Substances	Antineoplastic Agents ; Cathepsins (EC 3.4.-)
Language	English
Publishing date	2021-12-16
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms222413495
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Article ; Online: Lysosomal peptidases—intriguing roles in cancer progression and neurodegeneration

Janko Kos / Ana Mitrović / Milica Perišić Nanut / Anja Pišlar

FEBS Open Bio, Vol 12, Iss 4, Pp 708-

2022 Volume 738

Abstract	Lysosomal peptidases are hydrolytic enzymes capable of digesting waste proteins that are targeted to lysosomes via endocytosis and autophagy. Besides intracellular protein catabolism, they play more specific roles in several other cellular processes and pathologies, either within lysosomes, upon secretion into the cell cytoplasm or extracellular space, or bound to the plasma membrane. In cancer, lysosomal peptidases are generally associated with disease progression, as they participate in crucial processes leading to changes in cell morphology, signaling, migration, and invasion, and finally metastasis. However, they can also enhance the mechanisms resulting in cancer regression, such as apoptosis of tumor cells or antitumor immune responses. Lysosomal peptidases have also been identified as hallmarks of aging and neurodegeneration, playing roles in oxidative stress, mitochondrial dysfunction, abnormal intercellular communication, dysregulated trafficking, and the deposition of protein aggregates in neuronal cells. Furthermore, deficiencies in lysosomal peptidases may result in other pathological states, such as lysosomal storage disease. The aim of this review was to highlight the role of lysosomal peptidases in particular pathological processes of cancer and neurodegeneration and to address the potential of lysosomal peptidases in diagnosing and treating patients.
Keywords	cancer ; cathepsins ; lysosomes ; neurodegeneration ; peptidases ; Biology (General) ; QH301-705.5
Subject code	572 ; 610
Language	English
Publishing date	2022-04-01T00:00:00Z
Publisher	Wiley
Document type	Article ; Online
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Article ; Online: Cysteine Peptidase Cathepsin X as a Therapeutic Target for Simultaneous TLR3/4-mediated Microglia Activation.

Pišlar, Anja / Nedeljković, Biljana Božić / Perić, Mina / Jakoš, Tanja / Zidar, Nace / Kos, Janko

Molecular neurobiology

2022 Volume 59, Issue 4, Page(s) 2258–2276

Abstract: Microglia are resident macrophages in the central nervous system that are involved in immune responses driven by Toll-like receptors (TLRs). Microglia-mediated inflammation can lead to central nervous system disorders, and more than one TLR might be ... ...

Abstract	Microglia are resident macrophages in the central nervous system that are involved in immune responses driven by Toll-like receptors (TLRs). Microglia-mediated inflammation can lead to central nervous system disorders, and more than one TLR might be involved in these pathological processes. The cysteine peptidase cathepsin X has been recognized as a pathogenic factor for inflammation-induced neurodegeneration. Here, we hypothesized that simultaneous TLR3 and TLR4 activation induces synergized microglia responses and that these phenotype changes affect cathepsin X expression and activity. Murine microglia BV2 cells and primary murine microglia were exposed to the TLR3 ligand polyinosinic-polycytidylic acid (poly(I:C)) and the TLR4 ligand lipopolysaccharide (LPS), individually and simultaneously. TLR3 and TLR4 co-activation resulted in increased inflammatory responses compared to individual TLR activation, where poly(I:C) and LPS induced distinct patterns of proinflammatory factors together with different patterns of cathepsin X expression and activity. TLR co-activation decreased intracellular cathepsin X activity and increased cathepsin X localization at the plasma membrane with concomitant increased extracellular cathepsin X protein levels and activity. Inhibition of cathepsin X in BV2 cells by AMS36, cathepsin X inhibitor, significantly reduced the poly(I:C)- and LPS-induced production of proinflammatory cytokines as well as apoptosis. Additionally, inhibiting the TLR3 and TLR4 common signaling pathway, PI3K, with LY294002 reduced the inflammatory responses of the poly(I:C)- and LPS-activated microglia and recovered cathepsin X activity. We here provide evidence that microglial cathepsin X strengthens microglia activation and leads to subsequent inflammation-induced neurodegeneration. As such, cathepsin X represents a therapeutic target for treating neurodegenerative diseases related to excess inflammation.
MeSH term(s)	Animals ; Cysteine/metabolism ; Inflammation/metabolism ; Ligands ; Lipopolysaccharides/pharmacology ; Mice ; Microglia/metabolism ; Poly I-C/adverse effects ; Poly I-C/metabolism ; Toll-Like Receptor 3/metabolism ; Toll-Like Receptor 4/metabolism
Chemical Substances	Ligands ; Lipopolysaccharides ; TLR3 protein, mouse ; Toll-Like Receptor 3 ; Toll-Like Receptor 4 ; Cysteine (K848JZ4886) ; Poly I-C (O84C90HH2L)
Language	English
Publishing date	2022-01-23
Publishing country	United States
Document type	Journal Article
ZDB-ID	645020-9
ISSN	1559-1182 ; 0893-7648
ISSN (online)	1559-1182
ISSN	0893-7648
DOI	10.1007/s12035-021-02694-2
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Zs.A 2411: Show issues

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Article ; Online: Cathepsin X Activity Does Not Affect NK-Target Cell Synapse but Is Rather Distributed to Cytotoxic Granules

Tanja Jakoš / Mateja Prunk / Anja Pišlar / Janko Kos

International Journal of Molecular Sciences, Vol 22, Iss 13495, p

2021 Volume 13495

Abstract	Cathepsin X is a lysosomal peptidase that is involved in tumour progression and represents a potential target for therapeutic interventions. In addition, it regulates important functions of immune cells and is implicated in the modulation of tumour cell–immune cell crosstalk. Selective cathepsin X inhibitors have been proposed as prospective antitumour agents to prevent cancer progression; however, their impact on the antitumour immune response has been overlooked. Previous studies indicate that the migration and adhesion of T cells and dendritic cells are affected by diminished cathepsin X activity. Meanwhile, the influence of cathepsin X inhibition on natural killer (NK) cell function has not yet been explored. Here, we examined the localization patterns of cathepsin X and the role of its inhibitors on the cytotoxicity of cell line NK-92, which is used for adoptive cellular immunotherapy in cancer patients. NK-92 cells depend on lymphocyte function-associated antigen 1 (LFA-1) to form stable immunoconjugates with target cells, providing, in this way, optimal cytotoxicity. Since LFA-1 is a substrate for cathepsin X activity in other types of cells, we hypothesized that cathepsin X could disturb the formation of NK-92 immunoconjugates. Thus, we employed cathepsin X reversible and irreversible inhibitors and evaluated their effects on the NK-92 cell interactions with target cells and on the NK-92 cell cytotoxicity. We show that cathepsin X inhibition does not impair stable conjugate formation or the lytic activity of NK-92 cells. Similarly, the conjugate formation between Jurkat T cells and target cells was not affected by cathepsin X activity. Unlike in previous migration and adhesion studies on T cells, in NK-92 cells cathepsin X was not co-localized with LFA-1 at the plasma membrane but was, rather, redistributed to the cytotoxic granules and secreted during degranulation.
Keywords	cytotoxic cells ; cathepsin X ; NK-92 ; immunological synapse ; LFA-1 ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	570
Language	English
Publishing date	2021-12-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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