Document Detail

Human and mouse perforin are processed in part through cleavage by the lysosomal cysteine proteinase cathepsin L.
MedLine Citation:
PMID:  20497254     Owner:  NLM     Status:  MEDLINE    
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.
Spela Konjar; Vivien R Sutton; Sabine Hoves; Urška Repnik; Hideo Yagita; Thomas Reinheckel; Christoph Peters; Vito Turk; Boris Turk; Joseph A Trapani; Nataša Kopitar-Jerala
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Immunology     Volume:  131     ISSN:  1365-2567     ISO Abbreviation:  Immunology     Publication Date:  2010 Oct 
Date Detail:
Created Date:  2010-11-05     Completed Date:  2011-01-10     Revised Date:  2012-05-07    
Medline Journal Info:
Nlm Unique ID:  0374672     Medline TA:  Immunology     Country:  England    
Other Details:
Languages:  eng     Pagination:  257-67     Citation Subset:  IM    
Copyright Information:
© 2010 The Authors. Immunology © 2010 Blackwell Publishing Ltd.
Department of Biochemistry, Molecular and Structural Biology, Jozef Stefan Institute, Ljubljana, Slovenia.
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MeSH Terms
Biocatalysis / drug effects
Cathepsin L / antagonists & inhibitors,  genetics,  metabolism*
Cell Line, Tumor
Cysteine Proteinase Inhibitors / pharmacology
Cytotoxicity, Immunologic / drug effects,  genetics,  immunology
Egtazic Acid / pharmacology
Granzymes / metabolism
K562 Cells
Killer Cells, Natural / drug effects,  immunology,  metabolism
Leucine / analogs & derivatives,  pharmacology
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Ovalbumin / immunology
Peptide Fragments / immunology
Peptide Hydrolases / metabolism
Pore Forming Cytotoxic Proteins / genetics,  metabolism*
Recombinant Proteins / genetics,  metabolism
T-Lymphocytes, Cytotoxic / drug effects,  immunology
Reg. No./Substance:
0/Cysteine Proteinase Inhibitors; 0/OVA-8; 0/PRF1 protein, human; 0/Peptide Fragments; 0/Pore Forming Cytotoxic Proteins; 0/Recombinant Proteins; 0/perforin 1, mouse; 61-90-5/Leucine; 67-42-5/Egtazic Acid; 88321-09-9/aloxistatin; 9006-59-1/Ovalbumin; EC 3.4.-/Peptide Hydrolases; EC 3.4.21.-/Granzymes; EC protein, human; EC L; EC protein, mouse

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