Cytokine signaling through <i>Drosophila</i> Mthl10 ties lifespan to environmental stress.

Abstract

A systems-level understanding of cytokine-mediated, intertissue signaling is one of the keys to developing fundamental insight into the links between aging and inflammation. Here, we employed <i>Drosophila</i>, a routine model for analysis of cytokine signaling pathways in higher animals, to identify a receptor for the growth-blocking peptide (GBP) cytokine. Having previously established that the phospholipase C/Ca²⁺ signaling pathway mediates innate immune responses to GBP, we conducted a dsRNA library screen for genes that modulate Ca²⁺ mobilization in <i>Drosophila</i> S3 cells. A hitherto orphan G protein coupled receptor, Methuselah-like receptor-10 (Mthl10), was a significant hit. Secondary screening confirmed specific binding of fluorophore-tagged GBP to both S3 cells and recombinant Mthl10-ectodomain. We discovered that the metabolic, immunological, and stress-protecting roles of GBP all interconnect through Mthl10. This we established by <i>Mthl10</i> knockdown in three fly model systems: in hemocyte-like <i>Drosophila</i> S2 cells, <i>Mthl10</i> knockdown decreases GBP-mediated innate immune responses; in larvae, <i>Mthl10</i> knockdown decreases expression of antimicrobial peptides in response to low temperature; in adult flies, <i>Mthl10</i> knockdown increases mortality rate following infection with <i>Micrococcus luteus</i> and reduces GBP-mediated secretion of insulin-like peptides. We further report that organismal fitness pays a price for the utilization of Mthl10 to integrate all of these various homeostatic attributes of GBP: We found that elevated <i>GBP</i> expression reduces lifespan. Conversely, <i>Mthl10</i> knockdown extended lifespan. We describe how our data offer opportunities for further molecular interrogation of yin and yang between homeostasis and longevity.