Cystatin F is a cathepsin C-directed protease inhibitor regulated by proteolysis.
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.
Hamilton
Garth
G
Division of Cell Biology & Immunology, College of Life Sciences, University of Dundee, Dundee, UK.
Colbert
Jeff D
JD
Schuettelkopf
Alexander W
AW
Watts
Colin
C
D000595:Amino Acid Sequence; D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D016466:CHO Cells; D020789:Cathepsin C / Q000037:antagonists & inhibitors / Q000502:physiology*; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D015891:Cystatins / Q000378:metabolism*; D004705:Endocytosis / Q000502:physiology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010447:Peptide Hydrolases / Q000502:physiology*; D011480:Protease Inhibitors / Q000378:metabolism*; D020298:U937 Cells
D014408:Biomarkers, Tumor; C116891:CST7 protein, human; D015891:Cystatins; D011480:Protease Inhibitors; D010447:Peptide Hydrolases; D020789:Cathepsin C