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Glycosylation Directs Targeting and Activation of Cystatin F from Intracellular and Extracellular Sources
Author(s) -
Colbert Jeff D,
Plechanovová Anna,
Watts Colin
Publication year - 2009
Publication title -
traffic
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.677
H-Index - 130
eISSN - 1600-0854
pISSN - 1398-9219
DOI - 10.1111/j.1600-0854.2009.00881.x
Subject(s) - cystatin , extracellular , biology , biochemistry , cathepsin , intracellular , cystatin c , glycosylation , proteases , microbiology and biotechnology , secretion , cathepsin b , endocytic cycle , internalization , cysteine protease , endocytosis , enzyme , cell , renal function
Cystatin F is a cysteine protease inhibitor that is selectively expressed in immune cells and unlike other cystatin family members is targeted to a significant extent to intracellular compartments. Initially made as an inactive glycosylated disulfide‐linked dimer, cystatin F is converted to an active monomer by proteolytic cleavage following transport to the endosomal/lysosomal system. This active form of cystatin F targets cathepsin C/DPPI and probably other cathepsins in immune cells. We show that efficient targeting of cystatin F to the endocytic pathway is dependent not on its unique dimeric conformation but rather on its oligosaccharide chains. We demonstrate the unusual addition of N ‐linked sugars to an Asn‐X‐Cys motif in cystatin F and provide evidence that the mannose 6‐phosphate sorting machinery is used to divert cystatin F from the secretory pathway and to mediate its uptake from extracellular pools. These studies identify a function for the oligosaccharides on cystatin F and raise the possibility that cystatin F might regulate proteases in trans by secretion in an inactive form by one cell and subsequent internalization and activation by another cell.