Consistent activation of the β-catenin pathway by Salmonella type-three secretion effector protein AvrA in chronically infected intestine

Lü, Rong; Liu, Xingyin; Wu, Shaoping; Xia, Yinglin; Zhang, Yong Guo; Petrof, Elaine O.; Claud, Erika C.; Sun, Jun

doi:10.1152/ajpgi.00453.2011

Cited by 57 publications

(52 citation statements)

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“…In this model, Salmonella persistently promotes small intestinal and colonic epithelial proliferation in vivo over 10-27 weeks [180]. This study also showed that, under these conditions, Salmonella strains expressing AvrA enhance expression of Akt, potentiate phosphorylation and acetylation of β-catenin, induce β-catenin nuclear translocation, and increase transcription of target genes, which could be the explanation for increased proliferation.…”

Section: An Alphabetical Guide Tosupporting

confidence: 59%

Impact ofSalmonella entericaType III Secretion System Effectors on the Eukaryotic Host Cell

Ramos‐Morales

2012

ISRN Cell Biology

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Type III secretion systems are molecular machines used by many Gram-negative bacterial pathogens to inject proteins, known as effectors, directly into eukaryotic host cells. These proteins manipulate host signal transduction pathways and cellular processes to the pathogen's advantage. Salmonella enterica possesses two virulence-related type III secretion systems that deliver more than forty effectors. This paper reviews our current knowledge about the functions, biochemical activities, host targets, and impact on host cells of these effectors. First, the concerted action of effectors at the cellular level in relevant aspects of the interaction between Salmonella and its hosts is analyzed. Then, particular issues that will drive research in the field in the near future are discussed. Finally, detailed information about each individual effector is provided.

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Section: An Alphabetical Guide Tosupporting

confidence: 59%

Impact ofSalmonella entericaType III Secretion System Effectors on the Eukaryotic Host Cell

Ramos‐Morales

2012

ISRN Cell Biology

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“…Success of PD-1/PD-L1 blockade for treatment of melanoma depends in part on established T cell infiltration into tumors, which is disrupted by tumor-intrinsic WNT/β-catenin signaling [80]. Commensal gut bacteria can modulate WNT/β-catenin pathway and promote colon carcinogenesis [81, 82]. It is unknown if gut microbiota could extend such an influence to tumors outside the gastrointestinal tract, but it is conceivable that commensals at other sites (skin) could engage similar mechanisms to activate WNT/β-catenin in melanomas.…”

Section: Cancer Immunotherapy Is Influenced By Microbiotamentioning

confidence: 99%

Adapting Cancer Immunotherapy Models for the Real World

Klevorn

Teague

2016

Trends in Immunology

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Early experiments in mice predicted the success of checkpoint blockade immunotherapy in cancer patients. However, these same animal studies failed to accurately predict many of the limitations and toxicities of treatment. One of the likely reasons for this discrepancy is the nearly universal use of young healthy mice, which stand in stark contrast to diverse patient populations varying in age, weight, diet and hygiene. Because these variables impact immunity and metabolism, they also influence outcomes during immunotherapy and should be incorporated into the study design of preclinical experiments. Here, we discuss recent findings that highlight how efficacy and toxicity of cancer immunotherapy are affected by patient variation, and how distinct host environments can be better modeled in animal studies.

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“…The Wnt ligand receptor (Wnt5a-Fzd5) signaling in macrophages was reported to promote phagocytosis of bacteria and enhanced survival through lipid rafts with Rac1-phosphatidylinositol 3-kinase (PI3K)-IB kinase (IKK) activation (31). Others have demonstrated that Salmonella activates host ␤-catenin signaling; moreover, Salmonella type 3 secreted effectors AvrA and SopB can individually activate Wnt/␤-catenin signaling in epithelial cells, leading to increases of stem cells and proliferative cells and transdifferentiation of primed epithelial cells into M cells, respectively, to promote intestinal invasion (33)(34)(35)(36)(37). Wnt5a is known to activate canonical and noncanonical Wnt pathways and is linked to cytoskeletal modulation and proinflammatory cytokine activation, e.g., in human macrophages stimulated by Mycobacterium (38)(39)(40)(41)(42).…”

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confidence: 99%

Ehrlichia chaffeensis Exploits Canonical and Noncanonical Host Wnt Signaling Pathways To Stimulate Phagocytosis and Promote Intracellular Survival

et al. 2016

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Ehrlichia chaffeensis invades and survives in phagocytes by modulating host cell processes and evading innate defenses, but the mechanisms are not fully defined. Recently we have determined that E. chaffeensis tandem repeat proteins (TRPs) are type 1 secreted effectors involved in functionally diverse interactions with host targets, including components of the evolutionarily conserved Wnt signaling pathways. In this study, we demonstrated that induction of host canonical and noncanonical Wnt pathways by E. chaffeensis TRP effectors stimulates phagocytosis and promotes intracellular survival. After E. chaffeensis infection, canonical and noncanonical Wnt signalings were significantly stimulated during early stages of infection (1 to 3 h) which coincided with dephosphorylation and nuclear translocation of ␤-catenin, a major canonical Wnt signal transducer, and NFATC1, a noncanonical Wnt transcription factor. In total, the expression of ϳ44% of Wnt signaling target genes was altered during infec- Ehrlichia chaffeensis is an obligately intracellular bacterium responsible for the emerging life-threatening human zoonosis human monocytotropic ehrlichiosis (HME) (1). E. chaffeensis selectively infects mononuclear phagocytes and resides in early-endosome-like membrane-bound vacuoles (1). The mechanisms by which E. chaffeensis enters host cells, establishes persistent infection, and avoids host defenses are not completely understood but occur through functionally relevant host-pathogen interactions involving secreted ehrlichial tandem repeat protein (TRP) effectors that are posttranslationally modified by ubiquitin (Ub) and the small ubiquitin-like modifier (SUMO) (2-5). E. chaffeensis TRPs interact with a diverse group of human proteins associated with major cellular processes, including transcription, translation, protein trafficking, cell signaling, cytoskeleton organization, and apoptosis, indicating that they play a role in manipulating these important cellular processes to facilitate infection (6-8).E. chaffeensis TRPs were first recognized as antigens that elicit strong protective antibody responses during infection that are directed at continuous species-specific epitopes in tandem repeat regions (9-12). Subsequently, our understanding of the functional role of TRPs as effectors in pathobiology has been advanced through studies that have defined specific TRP-host protein and DNA interactions (4, 13). Notably, E. chaffeensis TRP120 and TRP32 interact with numerous host proteins and genes associated with the canonical and noncanonical Wnt signaling pathways. One of TRP32-interacting targets, deleted-in-azoospermia-associated protein 2 (DAZAP2), is a highly conserved protein that modulates gene transcription driven by Wnt/␤-catenin signaling effector T-cell factors (TCFs), and knockdown of host DAZAP2 by small interfering RNA (siRNA) reduced the E. chaffeensis load in infected cells (7,14). Several other TRP120-interacting host proteins, such as AT-rich interactive domain 1B (ARID1B), lysine (K)-specific demethylase...

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Consistent activation of the β-catenin pathway by Salmonella type-three secretion effector protein AvrA in chronically infected intestine

Abstract: Consistent activation of the ␤-catenin pathway by Salmonella typethree secretion effector protein AvrA in chronically infected intestine. Am

Cited by 57 publications

References 57 publications

Impact ofSalmonella entericaType III Secretion System Effectors on the Eukaryotic Host Cell

Impact ofSalmonella entericaType III Secretion System Effectors on the Eukaryotic Host Cell

Adapting Cancer Immunotherapy Models for the Real World

Ehrlichia chaffeensis Exploits Canonical and Noncanonical Host Wnt Signaling Pathways To Stimulate Phagocytosis and Promote Intracellular Survival

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