Theileria parasites secrete a prolyl isomerase to maintain host leukocyte transformation

• Published in: Nature (London) Vol. 520; no. 7547; pp. 378 - 382
• Main Authors: Marsolier, J., Perichon, M., DeBarry, J. D., Villoutreix, B. O., Chluba, J., Lopez, T., Garrido, C., Zhou, X. Z., Lu, K. P., Fritsch, L., Ait-Si-Ali, S., Mhadhbi, M., Medjkane, S., Weitzman, J. B.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.04.2015; Nature Publishing Group
• Subjects: 13/1; 13/95; 14/19; 631/326/417/2551; 631/67/70; 64/116; 96/1; 96/95; Animals; Cattle; Cell Line; Cell Transformation, Neoplastic - drug effects; Drug Resistance - genetics; Genomics; Health aspects; Host-Parasite Interactions; Host-parasite relationships; Humanities and Social Sciences; Humans; Identification and classification; Isomerases; letter; Leukocytes; Leukocytes - drug effects; Leukocytes - parasitology; Leukocytes - pathology; Life Sciences; multidisciplinary; Mutation; Naphthoquinones - pharmacology; NIMA-Interacting Peptidylprolyl Isomerase; Parasites; Parasites - drug effects; Parasites - enzymology; Parasites - pathogenicity; Peptides; Peptidylprolyl Isomerase - antagonists & inhibitors; Peptidylprolyl Isomerase - genetics; Peptidylprolyl Isomerase - metabolism; Protein Stability; Proteins; Proto-Oncogene Proteins c-jun - metabolism; Science; Signal transduction; Signal Transduction - drug effects; SKP Cullin F-Box Protein Ligases - metabolism; Theileria; Theileria - drug effects; Theileria - enzymology; Theileria - genetics; Theileria - pathogenicity; Transcription Factor AP-1 - metabolism; Ubiquitination; Xenograft Model Antitumor Assays; Zebrafish - embryology
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature14044

Parasites of the Theileria genus infect cattle and transform their host cells, a transformation that can be reversed by treatment with the drug buparvaquone; here, a Theileria homologue of the peptidyl-prolyl isomerase PIN1 is shown to be secreted into the host cell, where it promotes transformation and can be directly inhibited by buparvaquone. Link between theileriosis and cancer Protozoan parasites of the Theileria genus are pathogenic in cattle. Uniquely among eukaryotic parasites, Theileria can transform host leukocytes to produce proliferative and invasive phenotypes associated with JNK and AP-1 signalling pathways. The transformation can be reversed by the antitheilerial drug buparvaquone. Here Justine Marsolier et al . identify a homologue of the peptidyl-prolyl isomerase PIN1 in Theileria annulata (TaPIN1), showing that it is secreted into the host cell where it interacts with the host's ubiquitin ligase FBW7, resulting in the stabilization of c-JUN which promotes transformation. The authors also show that TaPIN1 is directly inhibited by buparvaquone, using in vitro and in vivo zebrafish xenograft experiments, and demonstrate that TaPIN1 is mutated in a drug-resistant strain. This work highlights a surprising link between parasites and host oncogenic pathways. 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 1 . 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 3 . 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.