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Nature. 2015 Apr 16;520(7547):378-82. doi: 10.1038/nature14044. Epub 2015 Jan 26.

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

Author information

1
Université Paris Diderot, Sorbonne Paris Cité, Epigenetics and Cell Fate, UMR 7216 CNRS, 75013 Paris, France.
2
Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, Georgia 30602, USA.
3
Université Paris Diderot, Sorbonne Paris Cité, Molécules Thérapeutiques in silico, INSERM UMR-S 973, 75013 Paris, France.
4
1] INSERM, UMR 866, Equipe labellisée Ligue contre le Cancer and Laboratoire d'Excellence LipSTIC, 21000 Dijon, France [2] University of Burgundy, Faculty of Medicine and Pharmacy, 21000 Dijon, France.
5
1] INSERM, UMR 866, Equipe labellisée Ligue contre le Cancer and Laboratoire d'Excellence LipSTIC, 21000 Dijon, France [2] University of Burgundy, Faculty of Medicine and Pharmacy, 21000 Dijon, France [3] Centre anticancéreux George François Leclerc, CGFL, 21000 Dijon, France.
6
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
7
Laboratoire de Parasitologie, Ecole Nationale de Médecine Vétérinaire, Université de la Manouba, 2020 Sidi Thabet, Tunisia.

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.

PMID:
25624101
PMCID:
PMC4401560
DOI:
10.1038/nature14044
[Indexed for MEDLINE]
Free PMC Article

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