ENAGenomicsKarydo TherapeutiX, Inc.https://www.ebi.ac.uk/ena/browser/view/PRJNA1023982Distant organs influence each other via inter-organ cross-talks. However, the salivary-glands function locally by secreting saliva for oral-hygiene/lubrication and food-digestion. Herein, we challenge this dogma. We find that the salivary-glands secrete a family of evolutionarily-conserved proteins of proline-rich low-complexity sequences (LCS), S-PRPs (Salivary Proline-Rich-Proteins), into saliva and blood. Using mouse models, we demonstrate that blood S-PRPs form unusually stable high-molecular-weight-complex and titrate the bone phosphate-levels in a diet-dependent manner. This S-PRPs function is also bolstered by a negative-feedback loop established with FGF23. Moreover, comprehensive multi-organ transcriptome analyses indicate their additional functions beyond mineral-homeostasis. In human, one of S-PRPs, PRB1, is associated with chronic kidney disease, a disease linked to mineral-disorders. Hence, our findings unveil a previously unappreciated 'endocrine-like' function of the salivary-glands and provide a mechanistic insight into their roles in the whole-body scale well-being. Furthermore, our results illustrate a physiological function of 'secreted', rather than typical intra-cellular, LCS proteins.ENAfalseSalivary proteins of low complexity sequences titrate homeostasis of distant organs2024-05-112024-05-11PRJNA1023982