Human and mouse perforin are processed in part through cleavage by the lysosomal cysteine proteinase cathepsin L

S Konjar; VR Sutton; S Hoves; U Repnik; H Yagita; T Reinheckel; C Peters; V Turk; B Turk; JA Trapani; N Kopitar-Jerala

Journal article

Human and mouse perforin are processed in part through cleavage by the lysosomal cysteine proteinase cathepsin L

S Konjar, VR Sutton, S Hoves, U Repnik, H Yagita, T Reinheckel, C Peters, V Turk, B Turk, JA Trapani, N Kopitar-Jerala

Immunology | Published : 2010

DOI: 10.1111/j.1365-2567.2010.03299.x

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)..

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University of Melbourne Researchers

Vivien Sutton Author

Joseph Trapani Author

Related Projects (2)

2007 PROGRAM GRANT - (IMMUNE REGULATION, EFFECTOR FUNCTION AND HUMAN IMMUNOTHERAPY)

The immune system plays an important role in protecting the host from viral and bacterial infections, and inhibits cancer onset and progress..

Promotion to SPRF

Grants

Awarded by Research Agency of the Republic of Slovenia

Awarded by National Health and Medical Research Council (NHMRC) of Australia

Awarded by NMHRC

Awarded by Deutsche Forschungsgemeinschaft

Funding Acknowledgements

The authors thank Eric Vivier and Phillip Bird for NK-92 and K562 cells; Mark Smyth for the YT 5 cell line, Garnett Suck for KHYG1, Frank Carbone for EL-4, Marko Mihelic for active recombinant mouse Cat L, James Powers for granzyme B substrate, and Jose Villadangos for making the CatL<SUP>-/-</SUP> mice available for Australian investigators. This work was supported by the Research Agency of the Republic of Slovenia, grant P-0140 (to V.T. and B.T.) and S.K. was supported by Slovenian human resources development and scholarship foundation, Slovenia. J.A.T. and V.R.S. are supported by a programme grant from the National Health and Medical Research Council (NHMRC; 454569) of Australia. J.A.T. received a senior fellowship (288999) from NMHRC. S.H. was supported by Deutsche Forschungsgemeinschaft (Ho 4007/1-1).