Cathepsin X cleaves the C-terminal dipeptide of alpha- and gamma-enolase and impairs survival and neuritogenesis of neuronal cells.
The cysteine carboxypeptidase cathepsin X has been recognized as an important player in degenerative processes during normal aging and in pathological conditions. In this study we identify isozymes alpha- and gamma-enolases as targets for cathepsin X. Cathepsin X sequentially cleaves C-terminal amino acids of both isozymes, abolishing their neurotrophic activity. Neuronal cell survival and neuritogenesis are, in this way, regulated, as shown on pheochromocytoma cell line PC12. Inhibition of cathepsin X activity increases generation of plasmin, essential for neuronal differentiation and changes the length distribution of neurites, especially in the early phase of neurite outgrowth. Moreover, cathepsin X inhibition increases neuronal survival and reduces serum deprivation induced apoptosis, particularly in the absence of nerve growth factor. On the other hand, the proliferation of cells is decreased, indicating induction of differentiation. Our study reveals enolase isozymes as crucial neurotrophic factors that are regulated by the proteolytic activity of cathepsin X.
University of Ljubljana, Faculty of Pharmacy, Ljubljana, Slovenia. natasa.obermajer@ffa.uni-lj.si
Natasa
N
Obermajer
Bojan
B
Doljak
Polona
P
Jamnik
Ursa Pecar
UP
Fonović
Janko
J
Kos
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001681:Biological Assay; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004151:Dipeptides / Q000737:chemistry / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D016501:Neurites / Q000187:drug effects / Q000201:enzymology*; D016716:PC12 Cells; D010751:Phosphopyruvate Hydratase / Q000737:chemistry / Q000378:metabolism*; D010958:Plasminogen / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D051381:Rats
D004151:Dipeptides; D004791:Enzyme Inhibitors; D010958:Plasminogen; D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K; C534133:Ctsk protein, rat; D010751:Phosphopyruvate Hydratase