Peptidoglycan-Sensing Receptors Trigger the Formation of Functional Amyloids of the Adaptor Protein Imd to Initiate Drosophila NF-κB Signaling.
Peptidoglycan-Sensing Receptors Trigger the Formation of Functional Amyloids of the Adaptor Protein Imd to Initiate Drosophila NF-κB Signaling.
复制标题
肽聚糖感应受体触发接头蛋白 Imd 功能性淀粉样蛋白的形成，启动果蝇 NF-kappa B 信号转导
DOI：
10.1016/j.immuni.2017.09.011
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发表时间：
2017-10-17
期刊：
影响因子：
32.4
通讯作者：
Silverman N
中科院分区：
文献类型：
--
作者：
Kleino A;Ramia NF;Bozkurt G;Shen Y;Nailwal H;Huang J;Napetschnig J;Gangloff M;Chan FK;Wu H;Li J;Silverman N
在果蝇的免疫应答中，细菌来源的二氨基苯甲酸型肽聚糖结合受体PGRP-LC和PGRP-LE，通过与接头蛋白Imd的相互作用，激活NF-κB同源蛋白，促进抗菌肽基因的强劲表达。PGRP-LC、PGRP-LE和Imd都含有一个与RIP同型相互作用基序（RHIM）相似的基序，RHIM是哺乳动物RIPK蛋白在坏死坏死过程中形成功能性淀粉样蛋白的结构域。在这里，我们发现尽管序列存在差异，这些果蝇隐性RHIMs在体外和细胞中形成淀粉样蛋白原纤维。淀粉样蛋白的形成是Imd下游信号传递所必需的，与哺乳动物的RHIMs相反，淀粉样蛋白与细胞死亡无关。此外，淀粉样蛋白的形成是一个可调节的步骤，可以被该途径的内源性反馈调节剂Pirk抑制。因此，不同的序列基序能够形成淀粉样信号平台，这些平台的形成可能在多个生物过程中存在一个调节点。Kleino等人表明，在识别细菌肽聚糖时，淀粉样蛋白的形成是激活果蝇Imd途径所必需的。淀粉样蛋白的形成涉及一个类似于坏死相关哺乳动物蛋白中发现的基序，并且可以负调控，这表明淀粉样蛋白信号平台可能在多个生物过程中存在一个调节点。
In the Drosophila immune response, bacterial derived diaminopimelic acid-type peptidoglycan binds the receptors PGRP-LC and PGRP-LE, which through interaction with the adaptor protein Imd leads to activation of the NF-κB homolog Relish and robust antimicrobial peptide gene expression. PGRP-LC, PGRP-LE, and Imd each contain a motif with some resemblance to the RIP Homotypic Interaction Motif (RHIM), a domain found in mammalian RIPK proteins forming functional amyloids during necroptosis. Here we found that despite sequence divergence, these Drosophila cryptic RHIMs formed amyloid fibrils in vitro and in cells. Amyloid formation was required for signaling downstream of Imd, and in contrast to the mammalian RHIMs, was not associated with cell death. Furthermore, amyloid formation constituted a regulatable step and could be inhibited by Pirk, an endogenous feedback regulator of this pathway. Thus, diverse sequence motifs are capable of forming amyloidal signaling platforms, and the formation of these platforms may present a regulatory point in multiple biological processes. Kleino et al. show that amyloid formation is required for activation of the Drosophila Imd pathway upon recognition of bacterial peptidoglycans. Amyloid formation involves a motif resembling one found in necroptosis-associated mammalian proteins and can be negatively regulated, suggesting that amyloidal signaling platforms may present a regulatory point in multiple biological processes.
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