Abstract
The prototypical M13 peptidase, human Neprilysin, functions as a transmembrane “ectoenzyme” that cleaves neuropeptides that regulate e.g. glucose metabolism, and has been linked to type 2 diabetes. The M13 family has undergone a remarkable, and conserved, expansion in the Drosophila genus. Here, we describe the function of Drosophila melanogaster Neprilysin-like 15 (Nepl15). Nepl15 is likely to be a secreted protein, rather than a transmembrane protein. Nepl15 has changes in critical catalytic residues that are conserved across the Drosophila genus and likely renders the Nepl15 protein catalytically inactive. Nevertheless, a knockout of the Nepl15 gene reveals a reduction in triglyceride and glycogen storage, with the effects likely occurring during the larval feeding period. Conversely, flies overexpressing Nepl15 store more triglycerides and glycogen. Protein modeling suggests that Nepl15 is able to bind and sequester peptide targets of catalytically active Drosophila M13 family members, peptides that are conserved in humans and Drosophila, potentially providing a novel mechanism for regulating the activity of neuropeptides in the context of lipid and carbohydrate homeostasis.
Highlights
Neprilysin is the founding member of the M13 family of zinc metalloendopeptidases that typically function as “ecto-enzymes”
A number of peptide targets of mammalian Neprilysins that are known to be involved in feeding behavior, appetite regulation, metabolism and energy homeostasis, have D. melanogaster counterparts that are linked to similar processes[10,13,14,15]
Most of the conserved Cys residues involved in disulfide bonds in HsNeprilysin and in HsECE-1 are found in the Drosophila Nepl[15] orthologs, suggesting that they contribute to promoting a similar tertiary structure[3,16,17,18,19,20,21]
Summary
Neprilysin is the founding member of the M13 family of zinc metalloendopeptidases that typically function as “ecto-enzymes”. Mammalian Neprilysin has a number of potential peptide targets involved in regulating neuronal function, appetite, metabolism, energy homeostasis and inflammation (e.g. tachykinins such as Substance P, galanin, cholecystokinin and neuropeptide Y)[4,5,6,7,8]. D. melanogaster have organs for digestion and nutrient absorption (the midgut). A number of peptide targets of mammalian Neprilysins that are known to be involved in feeding behavior, appetite regulation, metabolism and energy homeostasis, have D. melanogaster counterparts that are linked to similar processes[10,13,14,15]. Over-expression of Nepl[15] in certain tissues results in increases in triglyceride and glycogen storage in males. Our results are consistent with a role for Nepl[15] in regulating neuropeptide cleavage in the context of nutrient metabolism
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