Trypanosome invasion of mammalian cells requires activation of the TGF-β signaling pathway

Mao, Ming; Ewen, Mark E.; Pereira, M. E. A.

doi:10.1016/0169-4758(95)80003-4

Cited by 51 publications

(59 citation statements)

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“…However, early production of TGF-b negatively associates with disease outcome in some models of protozoan infection [18,19], and treatment of T. cruzi-infected mice with TGF-b results in increased mortality and blocks the protective effects of IFN-c treatment [20]. We chose to use DNRII mice in these studies to isolate the effects of TGF-b on T cells and avoid the potential complication of interfering with TGF-b-mediated entry of T. cruzi into host cells [21] or other non-T cell-mediated effects of universal TGF-b blockade.…”

Section: Discussionmentioning

confidence: 99%

TGF‐β regulates pathology but not tissue CD8⁺ T cell dysfunction during experimental Trypanosoma cruzi infection

et al. 2007

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Infection with the protozoan parasite Trypanosoma cruzi leads to chronic infection, with parasite persistence primarily in muscle tissue. CD8 + T cells isolated from muscle tissue of T. cruzi-infected mice display decreased production of IFN-c in response to T cell receptor engagement. The expression of TGF-b at the site of CD8 + T cell dysfunction and parasite persistence suggested that this immunoregulatory cytokine might play a role in these processes. Mice expressing a T cell-specific dominant negative TGF-b receptor type II (DNRII) were therefore infected with T. cruzi. Infection of DNRII mice resulted in massive CD8 + T cell proliferation, leading to increased numbers but decreased frequencies of antigen-specific CD8 + T cells in the spleen compared to wild-type mice. However, TGF-b unresponsiveness failed to restore effector functions of CD8 + T cells isolated from muscle tissue. Histological examination of skeletal muscle from T. cruziinfected DNRII mice revealed an extensive cellular infiltrate, and DNRII mice displayed higher susceptibility to infection. Overall, while TGF-b does not appear to be responsible for CD8 + T cell unresponsiveness in peripheral tissue in T. cruzi-infected mice, these data suggest a role for TGF-b in control of immunopathology in response to T. cruzi infection.

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Section: Discussionmentioning

confidence: 99%

TGF‐β regulates pathology but not tissue CD8⁺ T cell dysfunction during experimental Trypanosoma cruzi infection

et al. 2007

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“…Recent studies have provided extensive evidence that activation of signaling cascades in host cells plays a central role in the T. cruzi cell invasion mechanism (5,20,34). Mobilization of Ca 2ϩ from intracellular stores has been specifically implicated, since cell loading with Ca 2ϩ chelators and Ca 2ϩ store depletion by thapsigargin effectively inhibit trypomastigote entry (7,24,31).…”

Section: Discussionmentioning

confidence: 99%

Dual Role of Signaling Pathways Leading to Ca²⁺and Cyclic AMP Elevation in Host Cell Invasion byTrypanosoma cruzi

et al. 2000

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Cell invasion by the protozoan parasite Trypanosoma cruzi involves activation of host signaling pathways and the recruitment and fusion of lysosomes at the parasite entry site. A major signaling pathway regulating invasion of fibroblasts, epithelial cells, and myoblasts involves mobilization of Ca 2؉ from intracellular stores and requires the activity of a T. cruzi serine peptidase, oligopeptidase B (OPB). Deletion of the OPB gene results in a marked defect in trypomastigote virulence, consistent with a greatly reduced cell invasion capacity. Here we show that uptake by macrophages, on the other hand, is largely independent of OPB expression and sensitive to inhibition of by cytochalasin D. The residual invasion capacity of OPBnull trypomastigotes in fibroblasts still involves lysosome recruitment, although in a significantly delayed fashion. Transient elevations in intracellular Ca 2؉ concentrations were observed in host cells exposed to both wild-type and OPBnull trypomastigotes, but the signals triggered by the mutant parasites were less vigorous and delayed. The capacity of triggering elevation in host cell cyclic AMP (cAMP), however, was unaltered in OPBnull trypomastigotes. Modulation in cAMP levels preferentially affected the residual cell invasion capacity of OPBnull parasites, suggesting that this signaling pathway can play a dominant role in promoting cell invasion in the absence of the major OPB-dependent pathway.

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“…HaCaT and Mv1Lu cells were cultured in MEM/10% FBS. DR27-TR47 cells (23) were cultured in MEM/10% FBS with 200 g/ml G418. HEK293T and HaCaT cells were transfected by using Lipofectamine (Invitrogen), and Mv1Lu cells were transfected by using Lipofectin (Invitrogen).…”

Section: Methodsmentioning

confidence: 99%

Critical regulation of TGFβ signaling by Hsp90

Wrighton

Lin²,

Feng

2008

Proc. Natl. Acad. Sci. U.S.A.

117

105

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Transforming growth factor ␤ (TGF␤) controls a diverse set of cellular processes by activating TGF␤ type I (T␤RI) and type II (T␤RII) serine-threonine receptor kinases. Canonical TGF␤ signaling is mediated by Smad2 and Smad3, which are phosphorylated in their SXS motif by activated T␤RI. The 90-kDa heat-shock protein (Hsp90) is a molecular chaperone facilitating the folding and stabilization of many protein kinases and intracellular signaling molecules. Here, we present evidence identifying a critical role for Hsp90 in TGF␤ signaling. Inhibition of Hsp90 function by using small-molecule inhibitors such as 17-allylamino-17-demethoxygeldanamycin (17AAG), and also at the genetic level, blocks TGF␤-induced signaling and transcriptional responses. Furthermore, we identify T␤RI and T␤RII as Hsp90-interacting proteins in vitro and in vivo and demonstrate that inhibition of Hsp90 function increases T␤R ubiquitination and degradation dependent on the Smurf2 ubiquitin E3 ligase. Our data reveal an essential level of TGF␤ signaling regulation mediated by Hsp90 by its ability to chaperone T␤Rs and also implicate the use of Hsp90 inhibitors in blocking undesired activation of TGF␤ signaling in diseases.Smad ͉ Smurf ͉ tumor suppression ͉ degra T GF␤ signals through heteromeric complexes of transmembrane serine-threonine kinase receptors to control diverse developmental processes and the pathogenesis of many diseases. Within the receptor complex, the TGF␤ type II receptor (T␤RII) is constitutively active and phosphorylates the TGF␤ type I receptor (T␤RI) on serine-threonine residues in the GS domain in response to TGF␤. Activated T␤RI then phosphorylates Smad2 and Smad3

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Trypanosome invasion of mammalian cells requires activation of the TGF-β signaling pathway

Cited by 51 publications

References 0 publications

TGF‐β regulates pathology but not tissue CD8⁺ T cell dysfunction during experimental Trypanosoma cruzi infection

TGF‐β regulates pathology but not tissue CD8⁺ T cell dysfunction during experimental Trypanosoma cruzi infection

Dual Role of Signaling Pathways Leading to Ca²⁺and Cyclic AMP Elevation in Host Cell Invasion byTrypanosoma cruzi

Critical regulation of TGFβ signaling by Hsp90

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Trypanosome invasion of mammalian cells requires activation of the TGF-β signaling pathway

Cited by 51 publications

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TGF‐β regulates pathology but not tissue CD8+ T cell dysfunction during experimental Trypanosoma cruzi infection

TGF‐β regulates pathology but not tissue CD8+ T cell dysfunction during experimental Trypanosoma cruzi infection

Dual Role of Signaling Pathways Leading to Ca2+and Cyclic AMP Elevation in Host Cell Invasion byTrypanosoma cruzi

Critical regulation of TGFβ signaling by Hsp90

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TGF‐β regulates pathology but not tissue CD8⁺ T cell dysfunction during experimental Trypanosoma cruzi infection

TGF‐β regulates pathology but not tissue CD8⁺ T cell dysfunction during experimental Trypanosoma cruzi infection

Dual Role of Signaling Pathways Leading to Ca²⁺and Cyclic AMP Elevation in Host Cell Invasion byTrypanosoma cruzi