NleB, a bacterial effector with glycosyltransferase activity, targets GAPDH function to inhibit NF-κB activation.
NleB, a bacterial effector with glycosyltransferase activity, targets GAPDH function to inhibit NF-κB activation.
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DOI：
10.1016/j.chom.2012.11.010
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发表时间：
2013-01-16
影响因子：
30.3
通讯作者：
Hardwidge PR
中科院分区：
文献类型：
--
作者：
Gao X;Wang X;Pham TH;Feuerbacher LA;Lubos ML;Huang M;Olsen R;Mushegian A;Slawson C;Hardwidge PR
调节NF-κB依赖的反应是成功附着/消除(A/E)人致病性大肠杆菌和自然小鼠病原体轮状柠檬酸杆菌的关键。NleB是一种高度保守的A/E病原体III型分泌系统效应器，可抑制NF-κB的激活，但其机制尚不清楚。我们鉴定了哺乳动物糖酵解酶3-磷酸甘油醛脱氢酶(GAPDH)是一种NleB相互作用蛋白。此外，我们发现GAPDH与肿瘤坏死因子受体相关因子2(TRAF2)相互作用，TRAF2是肿瘤坏死因子-α介导的NF-κB激活所必需的蛋白质，并调节TRAF2的多泛素化。在感染过程中，NleB作为一种易位的N-乙酰-D-氨基葡萄糖(O-GlcNAc)转移酶来修饰GAPDH。NleB介导的GAPDHO-GlcN酰化干扰TRAF2-GAPDH相互作用，抑制TRAF2的多泛素化和NF-κB的激活。消除NleB O-GlcN酰化活性可减少小鼠轮状芽孢杆菌的定植。这些数据证明GAPDH是一种TRAF2信号辅助因子，并揭示了A/E病原体采用一种毒力策略来抑制依赖于NF-κB的宿主天然免疫反应。
Modulation of NF-κB-dependent responses is critical to the success of attaching/effacing (A/E) human pathogenic E. coli (EPEC and EHEC) and the natural mouse pathogen Citrobacter rodentium. NleB, a highly conserved type III secretion system effector of A/E pathogens, suppresses NF-κB activation, but the underlying mechanisms are unknown. We identified the mammalian glycolysis enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH) as an NleB interacting protein. Further, we discovered that GAPDH interacts with the TNF receptor associated factor 2 (TRAF2), a protein required for TNF-α-mediated NF-κB activation, and regulates TRAF2 polyubiquitination. During infection, NleB functions as a translocated N-acetyl-D-glucosamine (O-GlcNAc) transferase that modifies GAPDH. NleB-mediated GAPDH O-GlcNAcylation disrupts the TRAF2-GAPDH interaction to suppress TRAF2 polyubiquitination and NF-κB activation. Eliminating NleB O-GlcNAcylation activity attenuates C. rodentium colonization of mice. These data identify GAPDH as a TRAF2 signaling cofactor and reveal a virulence strategy employed by A/E pathogens to inhibit NF-κB dependent host innate immune responses.
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TAB1 的 O-GlcNAc 酰化调节 TAK1 介导的细胞因子释放。
影响因子：
11.4
作者：
Pathak, Shalini;Borodkin, Vladimir S.;Albarbarawi, Osama;Campbell, David G.;Ibrahim, Adel;van Aalten, Daan M. F.
通讯作者：
van Aalten, Daan M. F.
影响因子：
3.6
作者：
Deng, WY;Vallance, BA;Finlay, BB
通讯作者：
Finlay, BB
DOI：
10.1056/nejmra0707500
发表时间：
2008-10-30
期刊：
The New England journal of medicine
影响因子：
--
作者：
Kelly, Ciaran P;LaMont, J Thomas
通讯作者：
LaMont, J Thomas
影响因子：
16.6
作者：
Hart GW;Slawson C;Ramirez-Correa G;Lagerlof O
通讯作者：
Lagerlof O
影响因子：
6.7
作者：
Gao X;Wan F;Mateo K;Callegari E;Wang D;Deng W;Puente J;Li F;Chaussee MS;Finlay BB;Lenardo MJ;Hardwidge PR
通讯作者：
Hardwidge PR