Dynamic regulation of innate immune responses in Drosophila by Senju-mediated glycosylation
Dynamic regulation of innate immune responses in Drosophila by Senju-mediated glycosylation
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DOI：
10.1073/pnas.1424514112
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发表时间：
2015-04
期刊：
影响因子：
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通讯作者：
M. Yamamoto-Hino;Masatoshi Muraoka;S. Kondo;R. Ueda;H. Okano;S. Goto
中科院分区：
文献类型：
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作者：
M. Yamamoto-Hino;Masatoshi Muraoka;S. Kondo;R. Ueda;H. Okano;S. Goto
先天性免疫系统是抵抗病原体入侵的第一道防线。通过感染激活先天免疫应答和稳态期间的抑制被严格控制以消除病原体并防止炎症。我们发现宿主糖基化在激活免疫应答和维持先天免疫稳态中起重要作用。在稳定状态下，大量含半乳糖聚糖抑制免疫应答的不良活化;然而，免疫应答的活化导致含半乳糖聚糖水平降低，这是将免疫应答提高到足够水平所需的。我们的发现提示了一种通过糖基化状态的改变来调节先天免疫静止和激活的新机制。先天免疫系统是入侵病原体遇到的第一道防线。延迟和/或不充分的先天免疫应答可能导致无法对抗病原体，而过度和/或不适当的应答导致失控的炎症。因此，免疫应答从开始到消退都受到严格调节，并在稳态期间受到抑制。众所周知，存在于病原体上的聚糖在病原体识别以及宿主分子与微生物之间的相互作用中起重要作用;然而，宿主生物体的聚糖在先天免疫应答中的功能鲜为人知。在这里，我们表明，先天免疫静止和免疫反应的强度是由主机糖基化涉及一种新的UDP-半乳糖转运称为Senju控制。在参菊突变体中，含半乳糖聚糖的表达减少导致在没有免疫挑战的情况下Toll信号通路的过度激活。遗传上位性和生物化学分析表明，Senju调节Toll信号通路的一个步骤，将Toll配体Spatzle转化为其活性形式。有趣的是，免疫激发的野生型（WT）果蝇中的Toll激活减少了含半乳糖聚糖的表达。通过参过表达抑制去半乳糖基化导致抗微生物肽Drosomycin的Toll依赖性表达的诱导减少，并增加对革兰氏阳性菌感染的易感性。这些数据表明，参介导的半乳糖基化在稳态期间抑制不期望的Toll信号传导激活;然而，响应于感染的Toll激活导致去半乳糖基化，这将免疫应答提高到足够的水平，并有助于迅速消除病原体。
Significance The innate immune system is the first line of defense against invading pathogens. Activation of the innate immune response by infection and suppression during steady state are stringently controlled to eliminate pathogens and prevent inflammation. We found that host glycosylation plays an important role in the activation of immune responses and in maintaining innate immune homeostasis. In the steady state, a high amount of galactose-containing glycan suppresses undesirable activation of the immune response; however, activation of immune responses leads to reduced levels of galactose-containing glycan, which is needed for raising immune responses to an adequate level. Our finding suggests a novel mechanism for the regulation of innate immune quiescence and activation via changes in glycosylation status. 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.