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Proteomics of protein trafficking by in vivo tissue-specific labeling

By Ilia A. Droujinine, Dan Wang, Yanhui Hu, Namrata D Udeshi, Luye Mu, Tanya Svinkina, Rebecca Zeng, Tess Branon, Areya Tabatabai, Justin A Bosch, John M Asara, Alice Y. Ting, Steven A Carr, Norbert Perrimon

Posted 16 Apr 2020
bioRxiv DOI: 10.1101/2020.04.15.039933

Secreted interorgan communication factors encode key regulators of homeostasis. However, long-standing questions surround their origins/destinations, mechanisms of interactions, and the number of proteins involved. Progress has been hindered by the lack of methodologies for these factors' large-scale identification and characterization, as conventional approaches cannot identify low-abundance factors and the origins and destinations of secreted proteins. We established an in vivo platform to investigate secreted protein trafficking between organs proteome-wide, whereby engineered promiscuous biotin ligase BirA*G3 (a relative of TurboID) 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, we identified 51 putative muscle-secreted proteins from heads and 269 fat body-secreted proteins from legs/muscles, of which 60-70% have human orthologs. We demonstrate, in particular, that conserved fat body-derived novel interorgan communication factors CG31326, CG2145, and CG4332 promote muscle activity. Our results indicate that the communication network of secreted proteins is vast, and we identified systemic functions for a number of these factors. This approach is widely applicable to studies in interorgan, local and intracellular protein trafficking networks, non-conventional secretion, and to mammalian systems, under healthy or diseased states. ### Competing Interest Statement The authors have declared no competing interest.

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