IL-4 Independent Nuclear Translocalization of STAT6 in HeLa Cells by Entry of Toxoplasma gondii

Ahn, Hye‐Jin; Kim, Ji Yeon; Nam, Ho-Woo

doi:10.3347/kjp.2009.47.2.117

Cited by 11 publications

(10 citation statements)

References 35 publications

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“…We further demonstrate that a STAT6/ROP16 interaction can be detected from infected cells and that recombinant, purified ROP16 has intrinsic tyrosine kinase activity in vitro and can directly phosphorylate STAT6 on the crucial activation residue Tyr 641 . Together, these results indicate that ROP16 may directly activate STAT6 upon secretion into host cells; they also provide a molecular basis for observations by Ahn et al (37,38) and Saeij et al (4) that Toxoplasma induces rapid STAT6 activation in an invasiondependent manner. While this manuscript was in preparation, Yamamoto et al (39) described similar results for host STAT3.…”

Section: Discussionmentioning

confidence: 49%

Toxoplasma Rhoptry Protein 16 (ROP16) Subverts Host Function by Direct Tyrosine Phosphorylation of STAT6

Ong

Reese

Boothroyd

2010

Journal of Biological Chemistry

203

179

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The obligate intracellular parasite, Toxoplasma gondii, modulates host immunity in a variety of highly specific ways. Previous work revealed a polymorphic, injected parasite factor, ROP16, to be a key virulence determinant and regulator of host cell transcription. These properties were shown to be partially mediated by dysregulation of the host transcription factors STAT3 and STAT6, but the molecular mechanisms underlying this phenotype were unclear. Here, we use a Type I Toxoplasma strain deficient in ROP16 to show that ROP16 induces not only sustained activation but also an extremely rapid (within 1 min) initial activation of STAT6. Using recombinant wild-type and kinase-deficient ROP16, we demonstrate in vitro that ROP16 has intrinsic tyrosine kinase activity and is capable of directly phosphorylating the key tyrosine residue for STAT6 activation, Tyr 641 . Furthermore, ROP16 co-immunoprecipitates with STAT6 from infected cells. Taken together, these data strongly suggest that STAT6 is a direct substrate for ROP16 in vivo.Toxoplasma gondii, a ubiquitous, intracellular parasite of the phylum Apicomplexa, infects an estimated one-third of the human population as well as a broad range of warm-blooded animals. Infection is typically asymptomatic and chronic; however, severe and even fatal disease can result from acute infections of congenitally infected or immunocompromised hosts. Strikingly, Toxoplasma-induced inflammatory pathology in adult immunocompetent patients has also been reported (1, 2).Understanding the host/parasite interactions that underpin these various disease manifestations has become an area of active investigation, and recent work has implicated as key players a set of polymorphic proteins that are secreted from the apical organelles known as rhoptries (3). One of these, a putative serine-threonine kinase known as ROP16, was revealed as a parasite factor responsible for many changes in host gene expression (4). Much of the effect of ROP16 on transcription was found to depend on sustained activation of STAT3 and STAT6, two host transcription factors that can negatively regulate Th1 inflammatory responses. ROP16 is thus poised to mediate the inflammatory status of the host, an intriguing role for a parasite effector because Th1-driven immunopathology, not just uncontrolled parasite growth and dissemination, has been proposed to be a significant contributor to the disease outcome (5).Although the potential significance of the ROP16 effect on STATs is clear, the molecular mechanism by which it accomplishes this sustained activation was not apparent from the initial studies. STAT activation requires phosphorylation at specific, conserved tyrosine residues; this phosphorylation, which induces dimerization and nuclear translocation of the STATs, is canonically initiated and maintained in the cytosol by either receptorassociated tyrosine kinases (such as the JAKs) or non-receptor tyrosine kinases (e.g. Src family kinases) (6). The duration of STAT activation is usually limited by negative feedback beca...

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Section: Discussionmentioning

confidence: 49%

Toxoplasma Rhoptry Protein 16 (ROP16) Subverts Host Function by Direct Tyrosine Phosphorylation of STAT6

Ong

Reese

Boothroyd

2010

Journal of Biological Chemistry

203

179

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“…However, the parasites survive within the macrophages against various attacking arms induced by IFN-γ such as iNOS (Luder et al 2003) and indoleamine 2,3-dioxygenase (Chaves et al 2001;Silva et al 2002) in addition to NO-induced host cell apoptosis (Wurster et al 2002). A cytokine cross-regulation of IFN-γ/IL-4 cross can be postulated, but it is presumed that T. gondii does not activate IL-4 production in the infected individual based on the absence of symptoms such as asthma or eosinophilia related to IL-4 responses in T. gondii infection (Ahn et al 2009). Instead, T. gondii evolves to provoke STAT6 activation in the infecting cells without IL-4 stimulus to protect the parasite from toxoplasmacidal action of IFN-γ/ STAT1.…”

Section: Discussionmentioning

confidence: 97%

“…IFN-γ does not control intracellular growth of T. gondii completely, which enable to presume a certain cytokine cross-regulation or STAT cross-regulation within the infected cells. In the previous study, STAT6, a unique signaling mediator of IL-4 and biologically homologous to IL-13 (Guiter et al 2004), was phosphorylated and translocated into the nuclei of fibroblast cells by T. gondii infection in the absence of exogenous IL-4 (Ahn et al 2009). …”

Section: Introductionmentioning

confidence: 96%

STAT6 activation by Toxoplasma gondii infection induces the expression of Th2 C-C chemokine ligands and B clade serine protease inhibitors in macrophage

et al. 2009

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Toxoplasma gondii provoked rapid and sustained nuclear translocation of signal transducer and activator of transcription (STAT) 6, a central mediator of interleukin (IL)-4, in macrophage-differentiated human acute monocytic leukemia cells without exogenous IL-4 in western blot and immunofluorescence assay. Phosphorylation of STAT6 occurred immediately after the entry of T. gondii and only by live tachyzoites, not by killed or soluble extract. It was impeded by Janus kinase (JAK) 3 inhibitor and small interfering RNA (siRNA) of STAT6. It induced expression of IL-4 responsive genes such as IL-4R, CD40, and CD23. It also mediated expression of two large clusters of C-C chemokine ligands (CCLs) and serine protease inhibitors (SERPINs) in microarray of T. gondii-infected macrophages. CCL1, 2, 8, 13, and 22 and SPINT2, SERPINB3, B4, and B13 were increased by the infection and inhibited by the treatment of JAK3 inhibitor and siRNA-mediated STAT6 silencing, which suggested the expression was governed by STAT6 activation. Secreting those CCLs, T. gondii-infected macrophages may attract more monocytes and Th2 cells of CCR3 and CCR4 to enrich the Th2 environment nearby the infected macrophages, and induced SERPINs may participate in protection from intracellular damages produced by activated lysosomal enzymes and in the inhibition of caspase activity to block the apoptosis. This suggests that T. gondii exploits cytokine cross-regulation through STAT6 activation to obviate various toxoplasmacidal reactions by interferon-gamma.

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“…Recently Toxoplasma gondii infection was shown to induce STAT6 P-Y 641 and activation in HeLa cells independent of IL-4, but the mechanism was unclear (Ahn et al, 2009). Considering that in all tested cells STAT6 can be activated by virus and induces specific genes for immune cell homing, the role of STAT6 on this side now starts to emerge.…”

Section: Virus-activated Stat6 Induces Specific Chemokinesmentioning

confidence: 99%

Activation of STAT6 by STING Is Critical for Antiviral Innate Immunity

Chen

Sun

You

et al. 2011

Cell

329

283

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STAT6 plays a prominent role in adaptive immunity by transducing signals from extracellular cytokines. We now show that STAT6 is required for innate immune signaling in response to virus infection. Viruses or cytoplasmic nucleic acids trigger STING (also named MITA/ERIS) to recruit STAT6 to the endoplasmic reticulum, leading to STAT6 phosphorylation on Ser(407) by TBK1 and Tyr(641), independent of JAKs. Phosphorylated STAT6 then dimerizes and translocates to the nucleus to induce specific target genes responsible for immune cell homing. Virus-induced STAT6 activation is detected in all cell-types tested, in contrast to the cell-type specific role of STAT6 in cytokine signaling, and Stat6(-/-) mice are susceptible to virus infection. Thus, STAT6 mediates immune signaling in response to both cytokines at the plasma membrane, and virus infection at the endoplasmic reticulum.

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IL-4 Independent Nuclear Translocalization of STAT6 in HeLa Cells by Entry of Toxoplasma gondii

Cited by 11 publications

References 35 publications

Toxoplasma Rhoptry Protein 16 (ROP16) Subverts Host Function by Direct Tyrosine Phosphorylation of STAT6

Toxoplasma Rhoptry Protein 16 (ROP16) Subverts Host Function by Direct Tyrosine Phosphorylation of STAT6

STAT6 activation by Toxoplasma gondii infection induces the expression of Th2 C-C chemokine ligands and B clade serine protease inhibitors in macrophage

Activation of STAT6 by STING Is Critical for Antiviral Innate Immunity

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