Cathepsin X Activity Does Not Affect NK-Target Cell Synapse but Is Rather Distributed to Cytotoxic Granules
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 i...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-12-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/22/24/13495 |
| _version_ | 1797503802990919680 |
|---|---|
| author | Tanja Jakoš Mateja Prunk Anja Pišlar Janko Kos |
| author_facet | Tanja Jakoš Mateja Prunk Anja Pišlar Janko Kos |
| author_sort | Tanja Jakoš |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T03:55:33Z |
| format | Article |
| id | doaj.art-5e406214138e4bbc8d46f9ff50043973 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T03:55:33Z |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-5e406214138e4bbc8d46f9ff500439732023-11-23T08:47:13ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-12-0122241349510.3390/ijms222413495Cathepsin X Activity Does Not Affect NK-Target Cell Synapse but Is Rather Distributed to Cytotoxic GranulesTanja Jakoš0Mateja Prunk1Anja Pišlar2Janko Kos3Department of Pharmaceutical Biology, Faculty of Pharmacy, University of Ljubljana, 1000 Ljubljana, SloveniaDepartment of Biotechnology, Jožef Stefan Institute, 1000 Ljubljana, SloveniaDepartment of Pharmaceutical Biology, Faculty of Pharmacy, University of Ljubljana, 1000 Ljubljana, SloveniaDepartment of Pharmaceutical Biology, Faculty of Pharmacy, University of Ljubljana, 1000 Ljubljana, SloveniaCathepsin 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.https://www.mdpi.com/1422-0067/22/24/13495cytotoxic cellscathepsin XNK-92immunological synapseLFA-1 |
| spellingShingle | Tanja Jakoš Mateja Prunk Anja Pišlar Janko Kos Cathepsin X Activity Does Not Affect NK-Target Cell Synapse but Is Rather Distributed to Cytotoxic Granules International Journal of Molecular Sciences cytotoxic cells cathepsin X NK-92 immunological synapse LFA-1 |
| title | Cathepsin X Activity Does Not Affect NK-Target Cell Synapse but Is Rather Distributed to Cytotoxic Granules |
| title_full | Cathepsin X Activity Does Not Affect NK-Target Cell Synapse but Is Rather Distributed to Cytotoxic Granules |
| title_fullStr | Cathepsin X Activity Does Not Affect NK-Target Cell Synapse but Is Rather Distributed to Cytotoxic Granules |
| title_full_unstemmed | Cathepsin X Activity Does Not Affect NK-Target Cell Synapse but Is Rather Distributed to Cytotoxic Granules |
| title_short | Cathepsin X Activity Does Not Affect NK-Target Cell Synapse but Is Rather Distributed to Cytotoxic Granules |
| title_sort | cathepsin x activity does not affect nk target cell synapse but is rather distributed to cytotoxic granules |
| topic | cytotoxic cells cathepsin X NK-92 immunological synapse LFA-1 |
| url | https://www.mdpi.com/1422-0067/22/24/13495 |
| work_keys_str_mv | AT tanjajakos cathepsinxactivitydoesnotaffectnktargetcellsynapsebutisratherdistributedtocytotoxicgranules AT matejaprunk cathepsinxactivitydoesnotaffectnktargetcellsynapsebutisratherdistributedtocytotoxicgranules AT anjapislar cathepsinxactivitydoesnotaffectnktargetcellsynapsebutisratherdistributedtocytotoxicgranules AT jankokos cathepsinxactivitydoesnotaffectnktargetcellsynapsebutisratherdistributedtocytotoxicgranules |