RRC ID 49635
著者 Sung EJ, Ryuda M, Matsumoto H, Uryu O, Ochiai M, Cook ME, Yi NY, Wang H, Putney JW, Bird GS, Shears SB, Hayakawa Y.
タイトル Cytokine signaling through Drosophila Mthl10 ties lifespan to environmental stress.
ジャーナル Proc Natl Acad Sci U S A
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 Drosophila, 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 Drosophila 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 Mthl10 knockdown in three fly model systems: in hemocyte-like Drosophila S2 cells, Mthl10 knockdown decreases GBP-mediated innate immune responses; in larvae, Mthl10 knockdown decreases expression of antimicrobial peptides in response to low temperature; in adult flies, Mthl10 knockdown increases mortality rate following infection with Micrococcus luteus 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 GBP expression reduces lifespan. Conversely, Mthl10 knockdown extended lifespan. We describe how our data offer opportunities for further molecular interrogation of yin and yang between homeostasis and longevity.
巻・号 114(52)
ページ 13786-13791
公開日 2017-12-26
DOI 10.1073/pnas.1712453115
PII 1712453115
PMID 29229844
PMC PMC5748187
MeSH Animals Cytokines / genetics Cytokines / metabolism* Drosophila Proteins / genetics Drosophila Proteins / metabolism* Drosophila melanogaster Longevity / physiology* Receptors, G-Protein-Coupled / genetics Receptors, G-Protein-Coupled / metabolism* Stress, Physiological / physiology*
IF 9.412
引用数 16
リソース情報
ショウジョウバエ 17061R-2 17061R-3