Document Detail

Cystatin F is a cathepsin C-directed protease inhibitor regulated by proteolysis.
MedLine Citation:
PMID:  18256700     Owner:  NLM     Status:  MEDLINE    
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.
Garth Hamilton; Jeff D Colbert; Alexander W Schuettelkopf; Colin Watts
Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The EMBO journal     Volume:  27     ISSN:  1460-2075     ISO Abbreviation:  EMBO J.     Publication Date:  2008 Feb 
Date Detail:
Created Date:  2008-02-07     Completed Date:  2008-03-04     Revised Date:  2009-11-19    
Medline Journal Info:
Nlm Unique ID:  8208664     Medline TA:  EMBO J     Country:  England    
Other Details:
Languages:  eng     Pagination:  499-508     Citation Subset:  IM    
Division of Cell Biology & Immunology, College of Life Sciences, University of Dundee, Dundee, UK.
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MeSH Terms
Amino Acid Sequence
CHO Cells
Cathepsin C / antagonists & inhibitors,  physiology*
Cell Line
Cystatins / metabolism*
Endocytosis / physiology
Mice, Inbred C57BL
Molecular Sequence Data
Peptide Hydrolases / physiology*
Protease Inhibitors / metabolism*
Tumor Markers, Biological / metabolism*
U937 Cells
Grant Support
//Wellcome Trust
Reg. No./Substance:
0/CST7 protein, human; 0/Cystatins; 0/Protease Inhibitors; 0/Tumor Markers, Biological; EC 3.4.-/Peptide Hydrolases; EC C

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