Kleino Anni, Ramia Nancy F, Bozkurt Gunes, Shen Yanfang, Nailwal Himani, Huang Jing, Napetschnig Johanna, Gangloff Monique, Chan Francis Ka-Ming, Wu Hao, Li Jixi, Silverman Neal
Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Department of Pathology, Program in Immunology and Microbiology, University of Massachusetts Medical School, Worcester, MA 01655, USA.
Immunity. 2017 Oct 17;47(4):635-647.e6. doi: 10.1016/j.immuni.2017.09.011.
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.
在果蝇的免疫反应中，细菌衍生的二氨基庚二酸型肽聚糖与受体PGRP-LC和PGRP-LE结合，这两种受体通过与衔接蛋白Imd相互作用，导致NF-κB同源物Relish的激活以及强大的抗菌肽基因表达。PGRP-LC、PGRP-LE和Imd各自包含一个与RIP同源相互作用基序（RHIM）有些相似的基序，RIP同源相互作用基序是在哺乳动物RIPK蛋白中发现的一个结构域，在坏死性凋亡过程中形成功能性淀粉样蛋白。在这里，我们发现尽管序列存在差异，但这些果蝇的隐秘RHIMs在体外和细胞中都能形成淀粉样纤维。淀粉样蛋白的形成是Imd下游信号传导所必需的，并且与哺乳动物的RHIMs不同，它与细胞死亡无关。此外，淀粉样蛋白的形成构成了一个可调节的步骤，并且可以被Pirk抑制，Pirk是该途径的内源性反馈调节因子。因此，不同的序列基序能够形成淀粉样信号平台，并且这些平台的形成可能在多个生物学过程中呈现为一个调节点。
