Bacterial effector NleL promotes enterohemorrhagic E. coli-induced attaching and effacing lesions by ubiquitylating and inactivating JNK.
Xiangpeng ShengQing YouHongnian ZhuZeNan ChangQingrun LiHaifeng WangChen WangHongyan WangLijian HuiChongtao DuXiaoduo XieRong ZengAnning LinDongfang ShiKangcheng RuanJinghua YanGeorge Fu GaoFeng ShaoHuiying ZhaoPublished in: PLoS pathogens (2017)
As a major diarrheagenic human pathogen, enterohemorrhagic Escherichia coli (EHEC) produce attaching and effacing (A/E) lesions, characterized by the formation of actin pedestals, on mammalian cells. A bacterial T3SS effector NleL from EHEC O157:H7 was recently shown to be a HECT-like E3 ligase in vitro, but its biological functions and host targets remain elusive. Here, we report that NleL is required to effectively promote EHEC-induced A/E lesions and bacterial infection. Furthermore, human c-Jun NH2-terminal kinases (JNKs) were identified as primary substrates of NleL. NleL-induced JNK ubiquitylation, particularly mono-ubiquitylation at the Lys 68 residue of JNK, impairs JNK's interaction with an upstream kinase MKK7, thus disrupting JNK phosphorylation and activation. This subsequently suppresses the transcriptional activity of activator protein-1 (AP-1), which modulates the formation of the EHEC-induced actin pedestals. Moreover, JNK knockdown or inhibition in host cells complements NleL deficiency in EHEC infection. Thus, we demonstrate that the effector protein NleL enhances the ability of EHEC to infect host cells by targeting host JNK, and elucidate an inhibitory role of ubiquitylation in regulating JNK phosphorylation.
Keyphrases
- induced apoptosis
- signaling pathway
- cell death
- high glucose
- escherichia coli
- endothelial cells
- endoplasmic reticulum stress
- diabetic rats
- oxidative stress
- regulatory t cells
- dendritic cells
- drug induced
- cell cycle arrest
- gene expression
- inflammatory response
- binding protein
- pseudomonas aeruginosa
- cystic fibrosis
- small molecule
- tyrosine kinase
- immune response
- multidrug resistant