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, β-endorphin, and dynorphin, as well as in generating the POMC-derived peptide hormones ACTH and α-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.
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
Lydiane
L
Funkelstein
Margery
M
Beinfeld
Ardalan
A
Minokadeh
James
J
Zadina
Vivian
V
Hook
D000595:Amino Acid Sequence; D000818:Animals; D056668:Cathepsin L / Q000235:genetics / Q000378:metabolism*; D004745:Enkephalins / Q000235:genetics / Q000378:metabolism; D055785:Gene Knockdown Techniques; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009479:Neuropeptides / Q000096:biosynthesis* / Q000235:genetics; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D022142:Secretory Vesicles / Q000201:enzymology*
D004745:Enkephalins; D009479:Neuropeptides; D011498:Protein Precursors; D056668:Cathepsin L