Theileriaparasites secrete a prolyl isomerase to maintain host leukocyte transformation

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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,Theileriais the only genus that transforms its mammalian host cells1.Theileriainfection 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 buparvaquone3. We used comparative genomics to identify a homologue of the peptidyl-prolyl isomerase PIN1 inT. 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 performedin vitroandin silicoanalysis andin vivozebrafish 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 byTheileriaparasites to manipulate host oncogenic signalling.

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