Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2015 May 5;112(18):5809-14. doi: 10.1073/pnas.1424514112. Epub 2015 Apr 21.

Dynamic regulation of innate immune responses in Drosophila by Senju-mediated glycosylation.

Author information

1
Department of Life Science, Rikkyo University, Tokyo 171-8501, Japan;
2
Stem Cell Project Group, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan;
3
Invertebrate Genetics Laboratory, Genetic Strains Research Center, National Institute of Genetics, Mishima 411-8540, Japan; and.
4
Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan.
5
Department of Life Science, Rikkyo University, Tokyo 171-8501, Japan; Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan stgoto@rikkyo.ac.jp.

Abstract

The innate immune system is the first line of defense encountered by invading pathogens. Delayed and/or inadequate innate immune responses can result in failure to combat pathogens, whereas excessive and/or inappropriate responses cause runaway inflammation. Therefore, immune responses are tightly regulated from initiation to resolution and are repressed during the steady state. It is well known that glycans presented on pathogens play important roles in pathogen recognition and the interactions between host molecules and microbes; however, the function of glycans of host organisms in innate immune responses is less well known. Here, we show that innate immune quiescence and strength of the immune response are controlled by host glycosylation involving a novel UDP-galactose transporter called Senju. In senju mutants, reduced expression of galactose-containing glycans resulted in hyperactivation of the Toll signaling pathway in the absence of immune challenges. Genetic epistasis and biochemical analyses revealed that Senju regulates the Toll signaling pathway at a step that converts Toll ligand Spatzle to its active form. Interestingly, Toll activation in immune-challenged wild type (WT) flies reduced the expression of galactose-containing glycans. Suppression of the degalactosylation by senju overexpression resulted in reduced induction of Toll-dependent expression of an antimicrobial peptide, Drosomycin, and increased susceptibility to infection with Gram-positive bacteria. These data suggest that Senju-mediated galactosylation suppresses undesirable Toll signaling activation during the steady state; however, Toll activation in response to infection leads to degalactosylation, which raises the immune response to an adequate level and contributes to the prompt elimination of pathogens.

KEYWORDS:

Toll pathway; galactose; glycosylation; innate immunity; nucleotide sugar transporter

PMID:
25901322
PMCID:
PMC4426399
DOI:
10.1073/pnas.1424514112
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center