Drosophila H2Av negatively regulates the activity of the IMD pathway via facilitating Relish SUMOylation.
Drosophila H2Av negatively regulates the activity of the IMD pathway via facilitating Relish SUMOylation.
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果蝇 H2Av 通过促进 Relish SUMOylation 负向调节 IMD 通路的活性
DOI：
10.1371/journal.pgen.1009718
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发表时间：
2021-08
期刊：
影响因子：
4.5
通讯作者：
Ling E
中科院分区：
文献类型：
--
作者：
Tang R;Huang W;Guan J;Liu Q;Beerntsen BT;Ling E
昆虫依靠先天免疫反应来防御多种病原体。果蝇免疫的核心是抗菌肽 (AMP)，当病原体触发 Toll 或 IMD 两种广泛研究的信号通路中的任何一种时，抗菌肽就会释放到循环系统中。 Toll 途径对革兰氏阳性细菌和真菌的感染作出反应，而 IMD 途径则由革兰氏阴性细菌激活。在 IMD 途径激活过程中，NF-κB 样转录因子 Relish 被磷酸化，然后被裂解，这对于 IMD 依赖性 AMP 基因诱导至关重要。在这里，我们发现非常规组蛋白变体 H2Av 的功能丧失突变体上调无菌果蝇幼虫和成虫中 IMD 依赖性 AMP 基因的诱导。仔细剖析 IMD 通路后，我们发现 Relish 与 H2Av 具有上位关系。在 H2Av 突变幼虫中，SUMO 化下调，表明 SUMO 化在免疫表型中可能发挥作用。最终我们证明 Relish 大部分是在氨基酸 K823 上进行 SUMO 化的。潜在 SUMO 化位点的丢失会导致 Relish 在体内显着的自动激活。进一步的研究表明，H2Av 在与 SUMOylation 途径的 E3 成分 Su(var)2-10 物理相互作用后调节 Relish SUMOylation。生化分析表明 Relish 的 SUMO 化可防止其裂解和激活。我们的研究结果提出了一种新机制，H2Av 可以通过促进 NF-κB 样转录因子 Relish 的 SUMO 化来负调节，从而防止 IMD 依赖性 AMP 产生的自发激活。
Insects depend on the innate immune response for defense against a wide array of pathogens. Central to Drosophila immunity are antimicrobial peptides (AMPs), released into circulation when pathogens trigger either of the two widely studied signal pathways, Toll or IMD. The Toll pathway responds to infection by Gram-positive bacteria and fungi while the IMD pathway is activated by Gram-negative bacteria. During activation of the IMD pathway, the NF-κB-like transcription factor Relish is phosphorylated and then cleaved, which is crucial for IMD-dependent AMP gene induction. Here we show that loss-of-function mutants of the unconventional histone variant H2Av upregulate IMD-dependent AMP gene induction in germ-free Drosophila larvae and adults. After careful dissection of the IMD pathway, we found that Relish has an epistatic relationship with H2Av. In the H2Av mutant larvae, SUMOylation is down-regulated, suggesting a possible role of SUMOylation in the immune phenotype. Eventually we demonstrated that Relish is mostly SUMOylated on amino acid K823. Loss of the potential SUMOylation site leads to significant auto-activation of Relish in vivo. Further work indicated that H2Av regulates Relish SUMOylation after physically interacting with Su(var)2-10, the E3 component of the SUMOylation pathway. Biochemical analysis suggested that SUMOylation of Relish prevents its cleavage and activation. Our findings suggest a new mechanism by which H2Av can negatively regulate, and thus prevent spontaneous activation of IMD-dependent AMP production, through facilitating SUMOylation of the NF-κB like transcription factor Relish.
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发表时间：
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期刊：
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影响因子：
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