title: Intracellular Theileria annulata promote invasive cell motility through kinase regulation of the host actin cytoskeleton.
abstract: The intracellular, protozoan Theileria species parasites are the only eukaryotes known to transform another eukaryotic cell. One consequence of this parasite-dependent transformation is the acquisition of motile and invasive properties of parasitized cells in vitro and their metastatic dissemination in the animal, which causes East Coast Fever (T. parva) or Tropical Theileriosis (T. annulata). These motile and invasive properties of infected host cells are enabled by parasite-dependent, poorly understood F-actin dynamics that control host cell membrane protrusions. Herein, we dissected functional and structural alterations that cause acquired motility and invasiveness of T. annulata-infected cells, to understand the molecular basis driving cell dissemination in Tropical Theileriosis. We found that chronic induction of TNFα by the parasite contributes to motility and invasiveness of parasitized host cells. We show that TNFα does so by specifically targeting expression and function of the host proto-oncogenic ser/thr kinase MAP4K4. Blocking either TNFα secretion or MAP4K4 expression dampens the formation of polar, F-actin-rich invasion structures and impairs cell motility in 3D. We identified the F-actin binding ERM family proteins as MAP4K4 downstream effectors in this process because TNFα-induced ERM activation and cell invasiveness are sensitive to MAP4K4 depletion. MAP4K4 expression in infected cells is induced by TNFα-JNK signalling and maintained by the inhibition of translational repression, whereby both effects are parasite dependent. Thus, parasite-induced TNFα promotes invasive motility of infected cells through the activation of MAP4K4, an evolutionary conserved kinase that controls cytoskeleton dynamics and cell motility. Hence, MAP4K4 couples inflammatory signaling to morphodynamic processes and cell motility, a process exploited by the intracellular Theileria parasite to increase its host cell's dissemination capabilities.
authors.affiliation: Neuro-Oncology, Experimental Infectious Diseases and Cancer Research, University Children's Hospital Zürich, Zürich, Switzerland; Molecular Pathobiology, University of Bern, Bern, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
authors.forename: Min
authors.initials: M
authors.lastname: Ma
authors.affiliation: Neuro-Oncology, Experimental Infectious Diseases and Cancer Research, University Children's Hospital Zürich, Zürich, Switzerland; Molecular Pathobiology, University of Bern, Bern, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Baumgartner
mesh_terms: D008841:Actin Cytoskeleton / Q000201:enzymology* / Q000473:pathology; D000818:Animals; D002417:Cattle; D002465:Cell Movement / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D006790:Host-Parasite Interactions / Q000502:physiology*; D015151:Immunoblotting; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016796:Theileria annulata; D013801:Theileriasis / Q000378:metabolism* / Q000473:pathology; D014162:Transfection
chemical_list: D034741:RNA, Small Interfering; D020928:Mitogen-Activated Protein Kinases