Unique biological function of cathepsin L in secretory vesicles for biosynthesis of neuropeptides

Neuropeptides are essential for cell-cell communication in the nervous and neuroendocrine systems Production of active neuropeptides requires proteolytic processing of proneuropeptide precursors in secretory vesicles that produce store and release neuropeptides that regulate physiological functions This review describes recent findings indicating the prominent role of cathepsin L in secretory vesicles for production of neuropeptides from their protein precursors The role of cathepsin L in neuropeptide production was discovered using the strategy of activity based probes for proenkephalin-cleaving activity for identification of the enzyme protein by mass spectrometry The novel role of cathepsin L in secretory vesicles for neuropeptide production has been demonstrated in vivo by cathepsin L gene knockout studies cathepsin L gene expression in neuroendocrine cells and notably cathepsin L localization in neuropeptide-containing secretory vesicles Cathepsin L is Involved in producing opioid neuropeptides consisting of enkephalin beta-endorphin and dynorphin as well as in generating the POMC-derived peptide hormones ACTH and alpha-MSH In addition NPY CCK and catestatin neuropeptides utilize cathepsin L for their biosynthesis The neuropeptide-synthesizing functions of cathepsin L represent its unique activity in secretory vesicles which contrasts with its role in lysosomes Interesting evaluations of protease gene knockout studies in mice that lack cathepsin L compared to those lacking PC1/3 and PC2 (PC prohormone convertase) indicate the key role of cathepsin L in neuropeptide production Therefore dual cathepsin L and prohormone convertase protease pathways participate in neuropeptide production Significantly the recent new findings indicate cathepsin L as a novel proprotein convertase for production of neuropeptides that mediate cell-cell communication in health and disease (C) 2010 Elsevier Ltd All rights reserved