Heiko Harten

Neprilysin regulates peptide turnover

Project Title: Impact of Neprilyin on physiology

Funding Source: DFG SFB944, TP21

Principle Investigator: Heiko Harten with Annika Buhr, Ronja Schiemann

I am using Drosophila melanogaster as a model organism to understand the physiological functionality of metalloproteases in general and of neprilysins in particular. In addition to investigating their functional relevance during development, we are interested in understanding the regulatory impact of neprilysins on distinct physiological processes, such as muscle and heart contraction or energy metabolism.

Insulin and IGF signaling are critical to numerous developmental and physiological processes, with perturbations being pathognomonic of various diseases, including diabetes. Although the functional roles of the respective signaling pathways have been extensively studied, the control of insulin production and release is only partially understood. Herein, we show that in Drosophila expression of insulin-like peptides is regulated by neprilysin activity. Concomitant phenotypes of altered neprilysin expression included impaired food intake, reduced body size, and characteristic changes in the metabolite composition. Ectopic expression of a catalytically inactive mutant did not elicit any of the phenotypes, which confirms abnormal peptide hydrolysis as a causative factor. A screen for corresponding substrates of the neprilysin identified distinct peptides that regulate insulin-like peptide expression, feeding behavior, or both. The high functional conservation of neprilysins and their substrates renders the characterized principles applicable to numerous species, including higher eukaryotes and humans.

The movie shows regular heart beating in flies

Overexpression of Neprilyin induces cardiac arrhythmia. Neprilysin catalyses breakdown of small regulatory peptides in heart cells.

Interview with Heiko Harten (in German), NDR 2019