Neyen Claudine, Runchel Christopher, Schüpfer Fanny, Meier Pascal, Lemaitre Bruno
Global Health Institute, Swiss Federal Institute of Technology, Lausanne, Switzerland.
The Breakthrough Toby Robins Breast Cancer Research Centre, Institute of Cancer Research, London, UK.
Nat Immunol. 2016 Oct;17(10):1150-8. doi: 10.1038/ni.3536. Epub 2016 Aug 22.
The innate immune system needs to distinguish between harmful and innocuous stimuli to adapt its activation to the level of threat. How Drosophila mounts differential immune responses to dead and live Gram-negative bacteria using the single peptidoglycan receptor PGRP-LC is unknown. Here we describe rPGRP-LC, an alternative splice variant of PGRP-LC that selectively dampens immune response activation in response to dead bacteria. rPGRP-LC-deficient flies cannot resolve immune activation after Gram-negative infection and die prematurely. The alternative exon in the encoding gene, here called rPGRP-LC, encodes an adaptor module that targets rPGRP-LC to membrane microdomains and interacts with the negative regulator Pirk and the ubiquitin ligase DIAP2. We find that rPGRP-LC-mediated resolution of an efficient immune response requires degradation of activating and regulatory receptors via endosomal ESCRT sorting. We propose that rPGRP-LC selectively responds to peptidoglycans from dead bacteria to tailor the immune response to the level of threat.
先天免疫系统需要区分有害刺激和无害刺激，以便根据威胁程度调整其激活状态。果蝇如何利用单一肽聚糖受体PGRP-LC对死的和活的革兰氏阴性菌产生不同的免疫反应尚不清楚。在这里，我们描述了rPGRP-LC，它是PGRP-LC的一种选择性剪接变体，能选择性地抑制对死菌的免疫反应激活。缺乏rPGRP-LC的果蝇在革兰氏阴性菌感染后无法消除免疫激活，并过早死亡。编码基因中的可变外显子，在这里称为rPGRP-LC，编码一个衔接子模块，该模块将rPGRP-LC靶向膜微结构域，并与负调节因子Pirk和泛素连接酶DIAP2相互作用。我们发现，rPGRP-LC介导的有效免疫反应的消除需要通过内体ESCRT分选降解激活受体和调节受体。我们提出，rPGRP-LC选择性地响应死菌的肽聚糖，以根据威胁程度调整免疫反应。
