Konjar 2010 Immunology
| Konjar S, Sutton VR, Hoves S, Repnik U, Yagita H, Reinheckel T, Peters C, Turk V, Turk B, Trapani JA, Kopitar-Jerala N (2010) Human and mouse perforin are processed in part through cleavage by the lysosomal cysteine proteinase cathepsin L. Immunology 131:257-67. |
Konjar S, Sutton VR, Hoves S, Repnik U, Yagita H, Reinheckel T, Peters C, Turk V, Turk B, Trapani JA, Kopitar-Jerala N (2010) Immunology
Abstract: The pore-forming protein perforin is synthesized as an inactive precursor in natural killer (NK) cells and cytotoxic T lymphocytes (CTLs), and becomes active when a short C-terminal peptide is cleaved within acidic lysosome-like cytotoxic granules. Although it was shown more than a decade ago that this cleavage is pH dependent and can be inhibited by the generic cysteine cathepsin inhibitor E-64d, no protease capable of processing the perforin C terminus has been identified. Neither is it known whether a single protease is responsible or the processing has inbuilt redundancy. Here, we show that incubation of human NK cells and primary antigen-restricted mouse CTLs with the cathepsin L (CatL) inhibitor L1 resulted in a marked inhibition of perforin-dependent target cell death and reduced perforin processing. In vitro, CatL preferentially cleaved a site on full-length recombinant perforin close to its C terminus. The NK cells of mice deficient in CatL showed a reduction but not a complete absence of processed perforin, indicating that cysteine proteases other than CatL are also able to process perforin. We conclude that granule-bound cathepsins are essential for processing perforin to its active form, and that CatL is an important, but not exclusive, participant in this process.
© 2010 The Authors. Immunology © 2010 Blackwell Publishing Ltd.
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Organism: Mouse
