title: Theileria parasites secrete a prolyl isomerase to maintain host leukocyte transformation.
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.
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Epigenetics and Cell Fate, UMR 7216 CNRS, 75013 Paris, France.
authors.forename: J
authors.initials: J
authors.lastname: Marsolier
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Epigenetics and Cell Fate, UMR 7216 CNRS, 75013 Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Perichon
authors.affiliation: Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, Georgia 30602, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: DeBarry
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Molécules Thérapeutiques in silico, INSERM UMR-S 973, 75013 Paris, France.
authors.forename: B O
authors.initials: BO
authors.lastname: Villoutreix
authors.affiliation: 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.
authors.forename: J
authors.initials: J
authors.lastname: Chluba
authors.affiliation: 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.
authors.forename: T
authors.initials: T
authors.lastname: Lopez
authors.affiliation: 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.
authors.forename: C
authors.initials: C
authors.lastname: Garrido
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: X Z
authors.initials: XZ
authors.lastname: Zhou
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: K P
authors.initials: KP
authors.lastname: Lu
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Epigenetics and Cell Fate, UMR 7216 CNRS, 75013 Paris, France.
authors.forename: L
authors.initials: L
authors.lastname: Fritsch
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Epigenetics and Cell Fate, UMR 7216 CNRS, 75013 Paris, France.
authors.forename: S
authors.initials: S
authors.lastname: Ait-Si-Ali
authors.affiliation: Laboratoire de Parasitologie, Ecole Nationale de Médecine Vétérinaire, Université de la Manouba, 2020 Sidi Thabet, Tunisia.
authors.forename: M
authors.initials: M
authors.lastname: Mhadhbi
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Epigenetics and Cell Fate, UMR 7216 CNRS, 75013 Paris, France.
authors.forename: S
authors.initials: S
authors.lastname: Medjkane
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Epigenetics and Cell Fate, UMR 7216 CNRS, 75013 Paris, France.
authors.forename: J B
authors.initials: JB
authors.lastname: Weitzman
mesh_terms: D000818:Animals; D002417:Cattle; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D004351:Drug Resistance / Q000235:genetics; D006790:Host-Parasite Interactions; D006801:Humans; D007962:Leukocytes / Q000187:drug effects / Q000469:parasitology / Q000473:pathology*; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009285:Naphthoquinones / Q000494:pharmacology; D010271:Parasites / Q000187:drug effects / Q000201:enzymology / Q000472:pathogenicity; D019696:Peptidylprolyl Isomerase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016794:Theileria / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics / Q000472:pathogenicity*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D054875:Ubiquitination; D023041:Xenograft Model Antitumor Assays; D015027:Zebrafish / Q000196:embryology
chemical_list: D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009285:Naphthoquinones; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; C046326:buparvaquone; D044843:SKP Cullin F-Box Protein Ligases; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase