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Konjar 2010 Immunology

From Bioblast
Publications in the MiPMap
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.

ยป PMID: 20497254 Open Access

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.

ยฉ 2010 The Authors. Immunology ยฉ 2010 Blackwell Publishing Ltd.


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Organism: Mouse