Multi-omic mapping of Drosophila protein secretomes reveals tissue-specific origins and inter-organ trafficking

Secreted proteins regulate many aspects of animal biology and are attractive targets for biomarkers and therapeutics. However, comprehensively identifying the "secretome", along with their tissues of origin, remains extremely challenging. To address this, we employed multiple 'omics methods to define a tissue-secretome map of 535 blood plasma proteins derived from specific cell-types and organs in Drosophila melanogaster. This map was enabled by methodological improvements including a collection of transgenic flies to label endogenous secreted proteins in 10 major tissue types, large-scale blood isolation, whole animal snRNA-seq, and 40 CRISPR knock-in strains. Using this map, we identify features of circulating proteins: most originate from specific tissues including unusual sources (e.g. glia), many are uncharacterized, and some are shed ectodomains of transmembrane proteins. In addition, in vivo experiments revealed circulating proteins with tissue-specific expression, as well as proteins that are deposited in a different tissue from where they are synthesized, suggesting potential inter-organ functions. Our secretome map will serve as a resource to investigate blood protein function, discover candidate tissue-tissue communication signals, and mine for homologues of human biomarkers.