EspL is a bacterial cysteine protease effector that cleaves RHIM proteins to block necroptosis and inflammation.
EspL is a bacterial cysteine protease effector that cleaves RHIM proteins to block necroptosis and inflammation.
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DOI：
10.1038/nmicrobiol.2016.258
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发表时间：
2017-01-13
影响因子：
28.3
通讯作者：
Hartland EL
中科院分区：
文献类型：
--
作者：
Pearson JS;Giogha C;Mühlen S;Nachbur U;Pham CL;Zhang Y;Hildebrand JM;Oates CV;Lung TW;Ingle D;Dagley LF;Bankovacki A;Petrie EJ;Schroeder GN;Crepin VF;Frankel G;Masters SL;Vince J;Murphy JM;Sunde M;Webb AI;Silke J;Hartland EL
细胞死亡信号通路有助于组织的动态平衡，并提供天生的保护免受感染。RIPK1、RIPK3、TRIF和ZBP1/DAI等接头蛋白含有受体相互作用蛋白(RIP)同型相互作用基序(Rhim)，在细胞死亡和炎症信号转导中起关键作用。依赖Rhim的相互作用有助于推动一种被称为坏死性下垂的caspase非依赖形式的细胞死亡。在此，我们报道了致病性肠杆菌(EPEC)在感染过程中利用III型分泌系统(T3SS)效应子Espl降解含有RHIM、RIPK1、RIPK3、TRIF和ZBP1/DAI的蛋白质。这需要在Espl(Cys47，His131，Asp153)中有一个先前未被识别的三方半胱氨酸蛋白酶基序，该基序在这些蛋白质的Rhim内切割。细菌感染和/或Espl的异位表达导致RIPK1、RIPK3、TRIF和ZBP1/DAI的快速失活，并抑制肿瘤坏死因子、内毒素或聚(I：C)诱导的坏死性下垂和炎症信号。此外，EPEC感染抑制了肿瘤坏死因子诱导的MLKL的磷酸化和质膜定位。在体内，Espl半胱氨酸蛋白酶活性有助于EPEC样鼠病原体轮状柠檬酸杆菌对小鼠的持续定植。Espl的活性定义了在一系列细菌中发现的T3SS半胱氨酸蛋白酶效应物家族，并揭示了胃肠道病原体直接靶向依赖Rhim的炎症和坏死链信号通路的机制。
Cell death signalling pathways contribute to tissue homeostasis and provide innate protection from infection. Adaptor proteins such as RIPK1, RIPK3, TRIF and ZBP1/DAI that contain receptor-interacting protein (RIP) homotypic interaction motifs (RHIM) play a key role in cell death and inflammatory signalling . RHIM-dependent interactions help drive a caspase independent form of cell death termed necroptosis . Here we report that the bacterial pathogen enteropathogenic Escherichia coli (EPEC) uses the type III secretion system (T3SS) effector EspL to degrade the RHIM containing proteins, RIPK1, RIPK3, TRIF and ZBP1/DAI during infection. This required a previously unrecognised tripartite cysteine protease motif in EspL (Cys47, His131, Asp153) that cleaved within the RHIM of these proteins. Bacterial infection and/or ectopic expression of EspL led to rapid inactivation of RIPK1, RIPK3, TRIF and ZBP1/DAI and inhibition of TNF, LPS or poly(I:C)-induced necroptosis and inflammatory signalling. Furthermore, EPEC infection inhibited TNF-induced phosphorylation and plasma membrane localization of MLKL. In vivo, EspL cysteine protease activity contributed to persistent colonization of mice by the EPEC-like mouse pathogen Citrobacter rodentium. The activity of EspL defines a family of T3SS cysteine protease effectors found in a range of bacteria and reveals a mechanism by which gastrointestinal pathogens directly target RHIM-dependent inflammatory and necroptotic signalling pathways.
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