The Phosphothreonine Lyase Activity of a Bacterial Type III Effector Family

Li, Hongtao; Xu, Hao; Zhou, Yan; Zhang, Jie; Long, Chengzu; Li, Shuqin; Chen, She; Zhou, Jian‐Min; Shao, Feng

doi:10.1126/science.1138960

Cited by 378 publications

(375 citation statements)

References 18 publications

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“…P38‐dependent ASM activation upon infection is also in agreement with the observed stronger accumulation of ceramide in bystander cells, when compared with cells with replicating bacteria. Indeed, p38 activation in cells with internalized bacteria is modest due to the phosphothreonine‐lyase activity of the Shigella OspF effector protein (Arbibe et al , 2007; Li et al , 2007). …”

Section: Discussionmentioning

confidence: 99%

Stress‐induced host membrane remodeling protects from infection by non‐motile bacterial pathogens

et al. 2018

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While mucosal inflammation is a major source of stress during enteropathogen infection, it remains to be fully elucidated how the host benefits from this environment to clear the pathogen. Here, we show that host stress induced by different stimuli mimicking inflammatory conditions strongly reduces the binding of Shigella flexneri to epithelial cells. Mechanistically, stress activates acid sphingomyelinase leading to host membrane remodeling. Consequently, knockdown or pharmacological inhibition of the acid sphingomyelinase blunts the stress‐dependent inhibition of Shigella binding to host cells. Interestingly, stress caused by intracellular Shigella replication also results in remodeling of the host cell membrane, in vitro and in vivo, which precludes re‐infection by this and other non‐motile pathogens. In contrast, Salmonella Typhimurium overcomes the shortage of permissive entry sites by gathering effectively at the remaining platforms through its flagellar motility. Overall, our findings reveal host membrane remodeling as a novel stress‐responsive cell‐autonomous defense mechanism that protects epithelial cells from infection by non‐motile bacterial pathogens.

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Section: Discussionmentioning

confidence: 99%

Stress‐induced host membrane remodeling protects from infection by non‐motile bacterial pathogens

et al. 2018

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“…Shigella flexneri effector OspG, which is a protein kinase, targets ubiquitin-conjugated enzymes, thereby affecting phosphoIkBa degradation and subsequent NF-kB activation (43). OspF, another Shigella type III effector, was also shown to inactivate MAPKs, including ERK1/2, JNK, and p38, by irreversibly removing phosphate groups from the phosphothreonine, but not from the phosphotyrosine residue in the activation loop of MAPKs (25). But up to now, few mycobacterial effectors as well as their (16).…”

Section: Discussionmentioning

confidence: 99%

Mycobacterium tuberculosis Mce3E Suppresses Host Innate Immune Responses by Targeting ERK1/2 Signaling

Chai

Zhang

et al. 2015

The Journal of Immunology

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Crucial to the pathogenesis of the tuberculosis (TB)-causing pathogen Mycobacterium tuberculosis is its ability to subvert host immune defenses to promote its intracellular survival. The mammalian cell entry protein 3E (Mce3E), located in the region of difference 15 of the M. tuberculosis genome and absent in Mycobacterium bovis bacillus Calmette-Guérin, has an essential role in facilitating the internalization of mammalian cells by mycobacteria. However, relatively little is known about the role of Mce3E in modulation of host innate immune responses. In this study, we demonstrate that Mce3E inhibits the activation of the ERK1/2 signaling pathway, leading to the suppression of Tnf and Il6 expression, and the promotion of mycobacterial survival within macrophages. Mce3E interacts and colocalizes with ERK1/2 at the endoplasmic reticulum in a DEF motif (an ERK-docking motif)–dependent manner, relocates ERK1/2 from cytoplasm to the endoplasmic reticulum, and finally reduces the association of ERK1/2 with MEK1 and blocks the nuclear translocation of phospho-ERK1/2. A DEF motif mutant form of Mce3E (F294A) loses its ability to suppress Tnf and Il6 expression and to promote intracellular survival of mycobacteria. Inhibition of the ERK1/2 pathway in macrophages using U0126, a specific inhibitor of the ERK pathway, also leads to the suppressed Tnf and Il6 expression and the enhanced intracellular survival of mycobacteria. Taken together, these results suggest that M. tuberculosis Mce3E exploits the ERK1/2 signaling pathway to suppress host innate immune responses, providing a potential Mce3E–ERK1/2 interface–based drug target against M. tuberculosis.

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“…is an E3 ubiquitin ligase that targets the MAPK kinase Ste7 in yeast and interferes with nuclear factor B signaling in human cells (10,11). Furthermore, a number of type 3 effectors (HopAI1/OspF/ SpvC family) from plant and animal pathogens inactivate MAPKs by cleaving the C-OP bond of phosphothreonine at their TXY motif (Thr-Xaa-Tyr, where Xaa is any amino acid) in the activation loop (12). MAPK signal pathways are major elements of the innate immunity of the plant and play crucial roles in recognition of pathogens as well as in activation of plant defense responses (13,14).…”

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confidence: 99%

Functional Analysis of the Type 3 Effector Nodulation Outer Protein L (NopL) from Rhizobium sp. NGR234

Zhang

Chen

et al. 2011

Journal of Biological Chemistry

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Rhizobia are nitrogen-fixing bacteria that induce nodules on roots of legume host plants. Nodule initiation is triggered by rhizobial Nod factors, i.e. lipo-chitooligosaccharidic nodulation signals produced in response to host flavonoids in the rhizosphere (1). Additional symbiotic determinants produced by specific rhizobial strains often influence establishment of symbiosis in a host-specific manner. For example, rhizobial effector proteins secreted by bacterial secretion systems can significantly affect nodule initiation and nitrogen fixation on certain host plants (2). Various rhizobial strains possess a type 3 secretion system and deliver type 3 effector proteins into eukaryotic host cells (3, 4), a strategy common to many pathogenic Gramnegative bacteria (e.g. Yersinia spp., Shigella spp., Salmonella spp., and Pseudomonas spp.; Ref. 5).Once delivered into host cells, many type 3 effectors of pathogenic bacteria function as virulence factors, which manipulate the host cell by circumventing or suppressing innate immunity. Type 3 effectors may target the ubiquitination-26 S proteasome pathway, alter RNA metabolism, or interfere with protein kinases in host cells (6 -8). Various type 3 effectors target components of mitogen-activated protein kinase (MAPK) pathways. For example, YopJ of Yersinia spp. inactivates human MAPK kinase by acetylation of amino acid residues in the activation loop (9) and the IpaH 9.8 effector of Shigella spp. is an E3 ubiquitin ligase that targets the MAPK kinase Ste7 in yeast and interferes with nuclear factor B signaling in human cells (10,11). Furthermore, a number of type 3 effectors (HopAI1/OspF/ SpvC family) from plant and animal pathogens inactivate MAPKs by cleaving the C-OP bond of phosphothreonine at their TXY motif (Thr-Xaa-Tyr, where Xaa is any amino acid) in the activation loop (12). MAPK signal pathways are major elements of the innate immunity of the plant and play crucial roles in recognition of pathogens as well as in activation of plant defense responses (13,14). Overexpression of genes involved in MAPK signaling can result in induction of a hypersensitive response (HR), 3 i.e. rapid localized cell death. Overexpression of SIPK (salicylic acid-induced protein kinase) and NtMEK2 (the MAPK kinase upstream of SIPK) induced necrosis of tobacco leaves within a few hours (15)(16)(17)

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The Phosphothreonine Lyase Activity of a Bacterial Type III Effector Family

Cited by 378 publications

References 18 publications

Stress‐induced host membrane remodeling protects from infection by non‐motile bacterial pathogens

Stress‐induced host membrane remodeling protects from infection by non‐motile bacterial pathogens

Mycobacterium tuberculosis Mce3E Suppresses Host Innate Immune Responses by Targeting ERK1/2 Signaling

Functional Analysis of the Type 3 Effector Nodulation Outer Protein L (NopL) from Rhizobium sp. NGR234

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