Elucidating Protein Communication Between Organs and Organisms in Homeostasis and Stress

Interorgan communication;interorganism communication;peptides;proteins;proteomics;genetics

Droujinine, Ilia ; Sinclair, David

University:Havard University

Department:Medical Sciences

关键词: Interorgan communication;    interorganism communication;    peptides;    proteins;    proteomics;    genetics;   

Others  :  https://dash.harvard.edu/bitstream/handle/1/37365148/DROUJININE-DISSERTATION-2020.pdf?sequence=1&isAllowed=n

美国|英语

来源: Digital Access to Scholarship at Harvard

【 摘 要 】

Secreted proteins coordinate functions of organs and organisms, and compose a yet uncharacterized communication network. For example, in homeostasis, fat-derived adipokines leptin and adiponectin serve as inter-organ secreted metabolic regulators, and in behavior, major urinary proteins serve as inter-organism excreted pheromones regulating aggression. Secreted factors are also relevant for disease: resulting from poorly-characterized dysfunctional inter-organ signaling, obesity affects 40% of the US population. Despite their relevance for understanding novel biological processes and diseases, identifying the secreted proteins involved has been challenging. Existing analysis methods have serious limitations that preclude comprehensive identification of low-abundance factors and their origins and destinations. Thus, many additional physiologically- and disease-relevant factors remain to be identified. I established an in vivo global proteomic platform to investigate secreted protein trafficking between organs, whereby an engineered promiscuous biotin protein ligase biotinylates all proteins in a subcellular compartment of one tissue, and biotinylated proteins are affinity-enriched and identified from distal organs using quantitative mass spectrometry. Using this platform in Drosophila, I showed trafficking of low abundance (100-400 picomolar) insulin, and identified 269 fat body-secreted proteins in legs/muscles (of which 60-70% have human orthologs). I identified a previously-uncharacterized factor cDIP (common Dpr-interacting protein), which signals the starved state of the fat body to the Dpr10 receptor on muscles to regulate their activity and increased neurite coverage. This provides a direct link between these two organs to signal low energy storage. Thus, my biotin ligase approach can screen and identify specific ligand-receptor interactions and remote action by secreted proteins. Secreted proteins also coordinate functions of organisms. Animals use chemical cues from their environment and conspecifics to inform decisions necessary for survival. Much is known about how small volatile molecules and pheromones guide behavior; however, whether and how other molecules secreted by conspecifics can influence behavior is unclear. I showed that adult Drosophila males secrete a short, previously unannotated 69 amino-acid small open reading frame (sORF) peptide, termed the Male Peptide (MaleP), that is derived from a previously-considered long non-coding RNA. I found that MaleP originates from the adult testis and is sex-specific. Fly larvae detect picomolar concentrations of MaleP through the Or35a olfactory receptor neurons. MaleP affects the developmental progression of larvae as it promotes larval residence in food, benefitting survival when larvae experience low-nutrient food conditions. My study represents the first detailed description in any species of larvae sensing a peptide released by adult males.