Theileria parasites secrete a prolyl isomerase to maintain host leukocyte transformation

摘要

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 pheno-types are reversed by treatment with the theilericidal drug bupar-vaquone. 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 bupar-vaquone (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.%泰勒虫属的原生动物寄生虫对牛具有致病性。在真核寄生虫中独特的是,泰勒虫能转变寄主的白细胞,产生与JNK和AP-1信号传导通道相关的、具有增殖和侵袭能力的表现型。这种转变可以通过抗泰勒虫药物"Buparvaquone"逆转。在这项研究中,Justine Marsolier等人识别出"肽酰脯氦酰异构酶PIN1"在环形泰勒虫(Theileria annulata)中的一个同源物(TaPIN1),发现它被分泌到寄主细胞中,在其中它与寄主的泛素连接酶FBW7发生相互作用,导致c-JUN被稳定,这会促进转变。作者利用体外和活体斑马鱼异种移植实验还发现TaPINM能被"Buparvaquone"直接抑制,同时也显示TaPIN1在一个抗药性的种系中发生了突变。这项研究显示了寄生虫与寄主致癌通道之间一个令人意外的联系。