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

TY - JOUR

T1 - Cystatin F is a cathepsin C-directed protease inhibitor regulated by proteolysis

AU - Hamilton, Garth

AU - Colbert, Jeff D.

AU - Schuettelkopf, Alexander W.

AU - Watts, Colin

PY - 2008/2/6

Y1 - 2008/2/6

N2 - 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.

AB - 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.

KW - cathepsin

KW - cystatin

KW - lymphocytes

KW - proteolysis

KW - DIPEPTIDYL-PEPTIDASE-I

KW - RAY CRYSTAL-STRUCTURE

KW - DENDRITIC CELLS

KW - CYSTEINE PROTEINASES

KW - GENE-EXPRESSION

KW - SERIAL ANALYSIS

KW - MAST-CELL

KW - ACTIVATION

KW - ANTIGEN

KW - LYMPHOCYTES

UR - https://www.scopus.com/pages/publications/38949174026

U2 - 10.1038/sj.emboj.7601979

DO - 10.1038/sj.emboj.7601979

M3 - Article

C2 - 18256700

SN - 0261-4189

VL - 27

SP - 499

EP - 508

JO - EMBO Journal

JF - EMBO Journal

IS - 3

ER -