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Theileria parasites secrete a prolyl isomerase to maintain host leukocyte transformation.

Marsolier J, Perichon M, DeBarry JD, Villoutreix BO, Chluba J, Lopez T, Garrido C, Zhou XZ, Lu KP, Fritsch L, Ait-Si-Ali S, Mhadhbi M, Medjkane S, Weitzman JB - Nature (2015)

Bottom Line: Here we show that TaPIN1 is a bona fide prolyl isomerase and that it interacts with the host ubiquitin ligase FBW7, leading to its degradation and subsequent stabilization of c-JUN, which promotes transformation.We performed in vitro and in silico analysis and in vivo zebrafish xenograft experiments to demonstrate that TaPIN1 is directly inhibited by the anti-parasite drug buparvaquone (and other known PIN1 inhibitors) and is mutated in a drug-resistant strain.Prolyl isomerization is thus a conserved mechanism that is important in cancer and is used by Theileria parasites to manipulate host oncogenic signalling.

View Article: PubMed Central - PubMed

Affiliation: Université Paris Diderot, Sorbonne Paris Cité, Epigenetics and Cell Fate, UMR 7216 CNRS, 75013 Paris, France.

ABSTRACT
Infectious agents develop intricate mechanisms to interact with host cell pathways and hijack their genetic and epigenetic machinery to change host cell phenotypic states. Among the Apicomplexa phylum of obligate intracellular parasites, which cause veterinary and human diseases, Theileria is the only genus that transforms its mammalian host cells. Theileria infection of bovine leukocytes induces proliferative and invasive phenotypes associated with activated signalling pathways, notably JNK and AP-1 (ref. 2). The transformed phenotypes are reversed by treatment with the theilericidal drug buparvaquone. We used comparative genomics to identify a homologue of the peptidyl-prolyl isomerase PIN1 in T. annulata (TaPIN1) that is secreted into the host cell and modulates oncogenic signalling pathways. Here we show that TaPIN1 is a bona fide prolyl isomerase and that it interacts with the host ubiquitin ligase FBW7, leading to its degradation and subsequent stabilization of c-JUN, which promotes transformation. We performed in vitro and in silico analysis and in vivo zebrafish xenograft experiments to demonstrate that TaPIN1 is directly inhibited by the anti-parasite drug buparvaquone (and other known PIN1 inhibitors) and is mutated in a drug-resistant strain. Prolyl isomerization is thus a conserved mechanism that is important in cancer and is used by Theileria parasites to manipulate host oncogenic signalling.

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Original Blota. FromFigure 1b: TaPin1 protein was detected in the host cytoplasm and nucleus, in contrast Apicomplexan actin (TaActin). Bovine Histone H3 (nuclear) and Tubulin (cytoplasmic) proteins were controls.b. FromFigure 4a: Endogenous TaPin1 interacts with FBW7α isoform. Protein extracts from TBL3 expressing Flag-hFBW7 isoforms or Flag-Control “Con” were immunoprecipitated and immunoblotted with TaPin1 or Flag antibodies.c. FromFigure 4b: Inhibition of TaPin1 by Bup, Jug or DTM increased FBW7α protein levels and decreased c-Jun expression in TBL3 cells. Actin/Tubulin were loading controls.d. FromFigure 4c: Inhibition of FBW7 increases c-Jun protein levels in TBL3 cells, whereas ectopic FBW7α expression reduced c-Jun protein levels. Bovine actin/Tubulin were loading controls. Con = empty vector.e. FromFigure 4h: Efficiency of two independent si-c-Jun. Bovine Tubulin loading control.
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Figure 14: Original Blota. FromFigure 1b: TaPin1 protein was detected in the host cytoplasm and nucleus, in contrast Apicomplexan actin (TaActin). Bovine Histone H3 (nuclear) and Tubulin (cytoplasmic) proteins were controls.b. FromFigure 4a: Endogenous TaPin1 interacts with FBW7α isoform. Protein extracts from TBL3 expressing Flag-hFBW7 isoforms or Flag-Control “Con” were immunoprecipitated and immunoblotted with TaPin1 or Flag antibodies.c. FromFigure 4b: Inhibition of TaPin1 by Bup, Jug or DTM increased FBW7α protein levels and decreased c-Jun expression in TBL3 cells. Actin/Tubulin were loading controls.d. FromFigure 4c: Inhibition of FBW7 increases c-Jun protein levels in TBL3 cells, whereas ectopic FBW7α expression reduced c-Jun protein levels. Bovine actin/Tubulin were loading controls. Con = empty vector.e. FromFigure 4h: Efficiency of two independent si-c-Jun. Bovine Tubulin loading control.


Theileria parasites secrete a prolyl isomerase to maintain host leukocyte transformation.

Marsolier J, Perichon M, DeBarry JD, Villoutreix BO, Chluba J, Lopez T, Garrido C, Zhou XZ, Lu KP, Fritsch L, Ait-Si-Ali S, Mhadhbi M, Medjkane S, Weitzman JB - Nature (2015)

Original Blota. FromFigure 1b: TaPin1 protein was detected in the host cytoplasm and nucleus, in contrast Apicomplexan actin (TaActin). Bovine Histone H3 (nuclear) and Tubulin (cytoplasmic) proteins were controls.b. FromFigure 4a: Endogenous TaPin1 interacts with FBW7α isoform. Protein extracts from TBL3 expressing Flag-hFBW7 isoforms or Flag-Control “Con” were immunoprecipitated and immunoblotted with TaPin1 or Flag antibodies.c. FromFigure 4b: Inhibition of TaPin1 by Bup, Jug or DTM increased FBW7α protein levels and decreased c-Jun expression in TBL3 cells. Actin/Tubulin were loading controls.d. FromFigure 4c: Inhibition of FBW7 increases c-Jun protein levels in TBL3 cells, whereas ectopic FBW7α expression reduced c-Jun protein levels. Bovine actin/Tubulin were loading controls. Con = empty vector.e. FromFigure 4h: Efficiency of two independent si-c-Jun. Bovine Tubulin loading control.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4401560&req=5

Figure 14: Original Blota. FromFigure 1b: TaPin1 protein was detected in the host cytoplasm and nucleus, in contrast Apicomplexan actin (TaActin). Bovine Histone H3 (nuclear) and Tubulin (cytoplasmic) proteins were controls.b. FromFigure 4a: Endogenous TaPin1 interacts with FBW7α isoform. Protein extracts from TBL3 expressing Flag-hFBW7 isoforms or Flag-Control “Con” were immunoprecipitated and immunoblotted with TaPin1 or Flag antibodies.c. FromFigure 4b: Inhibition of TaPin1 by Bup, Jug or DTM increased FBW7α protein levels and decreased c-Jun expression in TBL3 cells. Actin/Tubulin were loading controls.d. FromFigure 4c: Inhibition of FBW7 increases c-Jun protein levels in TBL3 cells, whereas ectopic FBW7α expression reduced c-Jun protein levels. Bovine actin/Tubulin were loading controls. Con = empty vector.e. FromFigure 4h: Efficiency of two independent si-c-Jun. Bovine Tubulin loading control.
Bottom Line: Here we show that TaPIN1 is a bona fide prolyl isomerase and that it interacts with the host ubiquitin ligase FBW7, leading to its degradation and subsequent stabilization of c-JUN, which promotes transformation.We performed in vitro and in silico analysis and in vivo zebrafish xenograft experiments to demonstrate that TaPIN1 is directly inhibited by the anti-parasite drug buparvaquone (and other known PIN1 inhibitors) and is mutated in a drug-resistant strain.Prolyl isomerization is thus a conserved mechanism that is important in cancer and is used by Theileria parasites to manipulate host oncogenic signalling.

View Article: PubMed Central - PubMed

Affiliation: Université Paris Diderot, Sorbonne Paris Cité, Epigenetics and Cell Fate, UMR 7216 CNRS, 75013 Paris, France.

ABSTRACT
Infectious agents develop intricate mechanisms to interact with host cell pathways and hijack their genetic and epigenetic machinery to change host cell phenotypic states. Among the Apicomplexa phylum of obligate intracellular parasites, which cause veterinary and human diseases, Theileria is the only genus that transforms its mammalian host cells. Theileria infection of bovine leukocytes induces proliferative and invasive phenotypes associated with activated signalling pathways, notably JNK and AP-1 (ref. 2). The transformed phenotypes are reversed by treatment with the theilericidal drug buparvaquone. We used comparative genomics to identify a homologue of the peptidyl-prolyl isomerase PIN1 in T. annulata (TaPIN1) that is secreted into the host cell and modulates oncogenic signalling pathways. Here we show that TaPIN1 is a bona fide prolyl isomerase and that it interacts with the host ubiquitin ligase FBW7, leading to its degradation and subsequent stabilization of c-JUN, which promotes transformation. We performed in vitro and in silico analysis and in vivo zebrafish xenograft experiments to demonstrate that TaPIN1 is directly inhibited by the anti-parasite drug buparvaquone (and other known PIN1 inhibitors) and is mutated in a drug-resistant strain. Prolyl isomerization is thus a conserved mechanism that is important in cancer and is used by Theileria parasites to manipulate host oncogenic signalling.

Show MeSH
Related in: MedlinePlus