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

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 UDPgalactose 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.innate immunity | glycosylation | Toll pathway | nucleotide sugar transporter | galactose

Immune genes and divergent antimicrobial peptides in flies of the subgenus Drosophila

“…When no significant hits (E < 0.1) were returned, we extracted corresponding orthologues from FlyBase for D. virilis , and/or D. mojavensis, and/or D. grimshawi, or from the D. albomicans [23] , or D. guttifera genome [30], and again used BLASTn and tBLASTn. Sources used to generate a list of immune genes were: Lagueux et al [31], De Gregorio et al [32], Lemaitre and Hoffman [1], Starz-Gaiano et al [33], Valanne et al [34], Zaidman-Remy et al [35], Hughes [36], Marchal et al [37], An et al [38], Binggeli and Lemaitre [39], Amoyel et al [40], Salazar-Jaramillo et al [20], and Yamamoto-Hino et al [41]. …”

Spätzle-Processing Enzyme-independent Activation of the Toll Pathway in <i>Drosophila</i> Innate Immunity

“…The role of SPE in adult flies during infection is well understood; however, whether SPE is the only Spz-processing protease with a role in innate immunity remains unclear. We recently identified a new Drosophila mutant, senju 1 , in which Spz is converted to an active form in the absence of immune challenge, which leads to constitutive activation of the Toll pathway (Yamamoto-Hino et al, 2015). Accordingly, Toll activation in senju 1 larvae was completely suppressed in the absence of Spz, whereas it was not affected by the introduction of mutant SPE.…”

“…This result indicates that an unidentified protease may activate Spz in senju 1 larvae. In the present study, we investigated whether a Spz-processing protease besides SPE is active in immune-challenged larvae and adults using the SPE null allele SPE Sk6 , which was generated by the Cas9mediated gene editing system (Yamamoto-Hino et al, 2015).…”

N-linked glycosylation restricts the function of short gastrulation to bind and shuttle BMPs

“…N-linked glycans in Drosophila are less complex than in vertebrates (North et al, 2006;Aoki et al, 2007;Gagneux and Varki, 1999). Nonetheless, several enzymes in the N-glycosylation pathway have been reported to impair Drosophila development (Wandall et al, 2003;Tian and Ten Hagen, 2006;Yamamoto-Hino et al, 2015).…”