Cystatin F Regulates Proteinase Activity in IL-2-activated Natural Killer Cells
Katarina Maher, Spela Konjar, Colin Watts, Boris Turk and Natasa Kopitar-Jerala
Affiliation: Department of Biochemistry Molecular and Structural Biology, Jozef Stefan Institute, Jamova 39, 1000 Ljubljana, Slovenia.
Cystatin F is a unique member of the cystatin family of cysteine protease inhibitors, which is synthesized as an
inactive dimer and it is activated by N-terminal cleavage in the endolysosomes. It is expressed in the cells of the immune
system: myeloid cells and the cells involved in target cell killing: natural killer (NK) cells and cytotoxic T cells (CTLs).
Upon activation of the NK cells with interleukin 2 (IL-2), cystatin F was found upregulated and co-localized in cytotoxic
granules with cathepsin C (CatC) and CatV. However, cystatin F inhibits the CatC in cells only when its N-terminal part is
processed. Although cystatin F could inhibit both CatV and CatC, the IL-2 stimulation of the YT cells resulted in an increased
CatV activity, while the CatC activity was unchanged. The incubation of IL-2 activated NK cells with a cysteine
proteinase inhibitor E-64d increased the cystatin F dimer formation. Our results suggest that cystatin F not only inhibits
CatV, but it is processed by the CatV in order to inhibit the CatC activity in cytotoxic granules. The regulation of the CatC
activity in the cytotoxic granules of the NK cells by the cystatin F could be important for the processing and activation of
granule-associated serine proteases - granzymes.
Keywords: Cathepsin C, Cathepsin V, Cystatin F, Natural Killer Cells.
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