Abstract
The apicomplexan parasite Theileria annulata transforms infected host cells, inducing uncontrolled proliferation and clonal expansion of the parasitized cell population. Shortly after sporozoite entry into the target cell, the surrounding host cell membrane is dissolved and an array of host cell microtubules (MTs) surrounds the parasite, which develops into the transforming schizont. The latter does not egress to invade and transform other cells. Instead, it remains tethered to host cell MTs and, during mitosis and cytokinesis, engages the cell's astral and central spindle MTs to secure its distribution between the two daughter cells. The molecular mechanism by which the schizont recruits and stabilizes host cell MTs is not known. MT minus ends are mostly anchored in the MT organizing center, while the plus ends explore the cellular space, switching constantly between phases of growth and shrinkage (called dynamic instability). Assuming the plus ends of growing MTs provide the first point of contact with the parasite, we focused on the complex protein machinery associated with these structures. We now report how the schizont recruits end-binding protein 1 (EB1), a central component of the MT plus end protein interaction network and key regulator of host cell MT dynamics. Using a range of in vitro experiments, we demonstrate that T. annulata p104, a polymorphic antigen expressed on the schizont surface, functions as a genuine EB1-binding protein and can recruit EB1 in the absence of any other parasite proteins. Binding strictly depends on a consensus SxIP motif located in a highly disordered C-terminal region of p104. We further show that parasite interaction with host cell EB1 is cell cycle regulated. This is the first description of a pathogen-encoded protein to interact with EB1 via a bona-fide SxIP motif. Our findings provide important new insight into the mode of interaction between Theileria and the host cell cytoskeleton.
Highlights
The tick-borne Apicomplexan parasites, Theileria annulata and Theileria parva, are the causative agents of lymphoproliferative diseases of cattle, tropical Theileriosis and East Coast fever, that cause significant economic losses in large parts of Asia and Africa
This resulted in 19 candidates that were screened for the presence of an SxIP motif and representation in a T. annulata schizont proteome database obtained by mass spectrometry [29]
Even though p104 was originally identified as a protein expressed by T. parva sporozoites [30], T. annulata p104 could detected by mass spectrometry in Triton X-114 lysates of purified T. annulata schizonts enriched for membrane proteins [29]
Summary
The tick-borne Apicomplexan parasites, Theileria annulata and Theileria parva, are the causative agents of lymphoproliferative diseases of cattle, tropical Theileriosis and East Coast fever, that cause significant economic losses in large parts of Asia and Africa. T. annulata predominantly infects macrophages/monocytes and B-cells, while T. parva infects predominantly T-cells and B-cells Both species possess the unique capacity of transforming their host cells, inducing uncontrolled proliferation and resistance to apoptosis (reviewed in [1,2]). By associating with the mitotic apparatus during mitosis and cytokinesis, the parasite secures the equal distribution of the schizont between the two new daughter cells [4]. This process involves the recruitment and stable association of de novo synthesized astral and central spindle MTs with the schizont surface [5].
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