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Proc Natl Acad Sci U S A. 2017 Dec 26;114(52):13786-13791. doi: 10.1073/pnas.1712453115. Epub 2017 Dec 11.

Cytokine signaling through Drosophila Mthl10 ties lifespan to environmental stress.

Author information

1
Inositol Signaling Group, Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709.
2
The Analytical Research Center for Experimental Sciences, Saga University, Saga 840-8502, Japan.
3
Department of Applied Biological Sciences, Saga University, Saga 840-8502, Japan.
4
Radioisotope Division, Institute of Low Temperature Science, Hokkaido University, Sapporo 060-0819, Japan.
5
Protein Expression Core Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709; Biomanufacturing Research Institute and Technology Enterprise.
6
Biomanufacturing Research Institute and Technology Enterprise, North Carolina Central University, Durham, NC 27707.
7
Calcium Signaling Section, Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709.
8
Inositol Signaling Group, Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709; shears@niehs.nih.gov hayakayo@cc.saga-u.ac.jp.
9
Department of Applied Biological Sciences, Saga University, Saga 840-8502, Japan; shears@niehs.nih.gov hayakayo@cc.saga-u.ac.jp.

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.

KEYWORDS:

longevity; receptor; stress

PMID:
29229844
PMCID:
PMC5748187
DOI:
10.1073/pnas.1712453115
[Indexed for MEDLINE]
Free PMC Article

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