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Cystatin F Affects Natural Killer Cell Cytotoxicity.

ABSTRACT: Cystatin F is a cysteine peptidase inhibitor which, unlike other cystatin family members, is targeted to endosomal/lysosomal compartments. It is synthesized as an inactive disulfide-linked dimer which is then converted to an active monomer by proteolytic cleavage of 15 N-terminal residues. Cystatin F has been suggested to regulate the cytotoxicity of natural killer (NK) cells by inhibiting the major granzyme convertases, cathepsins C and H. To test this hypothesis, we prepared variants of cystatin F and analyzed their uptake, subcellular trafficking, and peptidase inhibition, as well as their impact on the cytotoxicity of NK-92 cells and primary NK cells. The N-glycosylation pattern is responsible for the secretion, uptake, and subcellular sorting of cystatin F in HeLa and Hek293 cells, whereas the legumain binding site had no effect on these processes. Active, N-terminally truncated, monomeric cystatin F can also be internalized by recipient cells and targeted to endo/lysosomes, affecting also cells lacking the activating peptidase. Cystatin F mutants capable of cell internalization and trafficking through the endo/lysosomal pathway significantly decreased cathepsin C and H activities, both in situ, following transfection and in trans, using conditioned media. Further, incubation of IL-2 stimulated NK-92 and primary NK cells with full-length and N-terminally truncated cystatin F mutants led to suppression of their granule-mediated cytotoxicity. This effect was most significant with the N-terminally truncated mutants. These results suggest that cystatin F can be an important mediator within tumor microenvironment affecting the cytotoxicity of NK cells and consequently antitumor immune response.

SUBMITTER: Perisic Nanut M

PROVIDER: S-EPMC5693851 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Cystatin F Affects Natural Killer Cell Cytotoxicity.

Perišić Nanut Milica M Sabotič Jerica J Švajger Urban U Jewett Anahid A Kos Janko J

Frontiers in immunology 20171113

Cystatin F is a cysteine peptidase inhibitor which, unlike other cystatin family members, is targeted to endosomal/lysosomal compartments. It is synthesized as an inactive disulfide-linked dimer which is then converted to an active monomer by proteolytic cleavage of 15 N-terminal residues. Cystatin F has been suggested to regulate the cytotoxicity of natural killer (NK) cells by inhibiting the major granzyme convertases, cathepsins C and H. To test this hypothesis, we prepared variants of cystat ...[more]

PMID: 29180998

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Project description:High metastatic potential and resistance to immunotherapy lead to poor survival in patients with ovarian cancer. Angiopoietin-like protein 3 is aberrantly expressed and exerts diverse roles in the progression of several cancers. However, its function in ovarian cancer is unknown. Here, decreased expression of angiopoietin-like protein 3 was observed in ovarian cancer tissues and cells. Moreover, patients with high expression of angiopoietin-like protein 3 had longer overall survival and progression-free survival, indicating a good prognosis for patients. Furthermore, angiopoietin-like protein 3 overexpression inhibited ovarian cancer cell proliferation. Concomitantly, high invasion and the occurrence of epithelial-to-mesenchymal transition of cancer cells were restrained after angiopoietin-like protein 3 elevation. Up-regulation of angiopoietin-like protein 3 expression further increased interleukin 2-treated natural killer cell activation by increasing CD69 expression and production of interferon gamma and tumor necrosis factor-alpha when natural killer cells were co-cultured with ovarian cancer cells. Importantly, angiopoietin-like protein 3 overexpression enhanced natural killer cell-evoked cytotoxicity and apoptosis of cancer cells, indicating the pro-tumor killing ability of angiopoietin-like protein 3 for natural killer cells. Mechanistically, angiopoietin-like protein 3 elevation inhibited activation of the Janus Kinase/Signal transducer and activator of transcription 3 signaling in ovarian cancer cells by inhibiting protein expression of phospho-Janus Kinase 2, phospho-Signal transducer and activator of transcription 3, downstream matrix metallopeptidase 2 and programmed cell death 1. Moreover, blocking the Janus Kinase/Signal transducer and activator of transcription 3 pathway via their inhibitor Stattic restrained ovarian cancer cell proliferation, invasion, epithelial-to-mesenchymal transition, and promoted natural killer cell killing to ovarian cancer cells. Thus, these findings reveal that angiopoietin-like protein 3 may act as an anti-oncogenic regulator to inhibit the metastatic potential and enhance the susceptibility of ovarian cancer cells to natural killer cell-mediated killing. Consequently, angiopoietin-like protein 3 may regulate metastatic potential and immune escape from natural killer cells, indicating a promising therapeutic strategy for ovarian cancer.

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Cystatin F Affects Natural Killer Cell Cytotoxicity.

Publications

Cystatin F Affects Natural Killer Cell Cytotoxicity.

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