1. Major Role of Cathepsin L for Producing the Peptide Hormones ACTH, β-Endorphin, and α-MSH, Illustrated by Protease Gene Knockout and Expression*
- Author
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Urs D Lichtenauer, Vivian Hook, Lydiane Funkelstein, Christoph Peters, Charles Mosier, Felix Beuschlein, Thomas Toneff, Thomas Reinheckel, and Shin-Rong Hwang
- Subjects
medicine.medical_specialty ,endocrine system ,Pro-Opiomelanocortin ,Cathepsin L ,Cathepsin D ,Gene Expression ,Adrenocorticotropic hormone ,Peptide hormone ,Biochemistry ,Mice ,Anterior pituitary ,Proopiomelanocortin ,Adrenocorticotropic Hormone ,Cathepsin H ,Internal medicine ,medicine ,Animals ,Molecular Biology ,Cathepsin ,Mice, Knockout ,biology ,Protein Synthesis, Post-Translational Modification, and Degradation ,Secretory Vesicles ,beta-Endorphin ,Cell Biology ,Cathepsins ,Cysteine Endopeptidases ,medicine.anatomical_structure ,Endocrinology ,alpha-MSH ,Pituitary Gland ,biology.protein ,Cattle ,Lysosomes ,hormones, hormone substitutes, and hormone antagonists - Abstract
The pituitary hormones adrenocorticotropic hormone (ACTH), beta-endorphin, and alpha-melanocyte stimulating hormone (alpha-MSH) are synthesized by proteolytic processing of their common proopiomelanocortin (POMC) precursor. Key findings from this study show that cathepsin L functions as a major proteolytic enzyme for the production of POMC-derived peptide hormones in secretory vesicles. Specifically, cathepsin L knock-out mice showed major decreases in ACTH, beta-endorphin, and alpha-MSH that were reduced to 23, 18, and 7% of wild-type controls (100%) in pituitary. These decreased peptide levels were accompanied by increased levels of POMC consistent with proteolysis of POMC by cathepsin L. Immunofluorescence microscopy showed colocalization of cathepsin L with beta-endorphin and alpha-MSH in the intermediate pituitary and with ACTH in the anterior pituitary. In contrast, cathepsin L was only partially colocalized with the lysosomal marker Lamp-1 in pituitary, consistent with its extralysosomal function in secretory vesicles. Expression of cathepsin L in pituitary AtT-20 cells resulted in increased ACTH and beta-endorphin in the regulated secretory pathway. Furthermore, treatment of AtT-20 cells with CLIK-148, a specific inhibitor of cathepsin L, resulted in reduced production of ACTH and accumulation of POMC. These findings demonstrate a prominent role for cathepsin L in the production of ACTH, beta-endorphin, and alpha-MSH peptide hormones in the regulated secretory pathway.
- Published
- 2008