Cystatin F is a cathepsin C-directed protease inhibitor regulated by proteolysis

Garth Hamilton, Jeff D. Colbert, Alexander W. Schuettelkopf, Colin Watts (Lead / Corresponding author)

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    73 Citations (Scopus)

    Abstract

    Cystatins are a family of naturally occurring cysteine protease inhibitors, yet the target proteases and biological processes they regulate are poorly understood. Cystatin F is expressed selectively in immune cells and is the only cystatin to be synthesised as an inactive disulphide-linked dimeric precursor. Here, we show that a major target of cystatin F in different immune cell types is the aminopeptidase cathepsin C, which regulates the activation of effector serine proteases in T cells, natural killer cells, neutrophils and mast cells. Surprisingly, recombinant cystatin F was unable to inhibit cathepsin C in vitro even though overexpression of cystatin F suppressed cellular cathepsin C activity. We predicted, using structural models, that an N-terminal processing event would be necessary before cystatin F can engage cathepsin C and we show that the intracellular form of cystatin F indeed has a precise N-terminal truncation that creates a cathepsin C inhibitor. Thus, cystatin F is a latent protease inhibitor itself regulated by proteolysis in the endocytic pathway. By targeting cathepsin C, it may regulate diverse immune cell effector functions.

    Original languageEnglish
    Pages (from-to)499-508
    Number of pages10
    JournalEMBO Journal
    Volume27
    Issue number3
    DOIs
    Publication statusPublished - 6 Feb 2008

    Keywords

    • cathepsin
    • cystatin
    • lymphocytes
    • proteolysis
    • DIPEPTIDYL-PEPTIDASE-I
    • RAY CRYSTAL-STRUCTURE
    • DENDRITIC CELLS
    • CYSTEINE PROTEINASES
    • GENE-EXPRESSION
    • SERIAL ANALYSIS
    • MAST-CELL
    • ACTIVATION
    • ANTIGEN
    • LYMPHOCYTES

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