miR-126-5p by direct targeting of JNK- interacting protein-2 (JIP-2) plays a key role in Theileria-infected macrophage virulence

Abstract : Theileria annulata is an apicomplexan parasite that infects and transforms bovine macrophages that disseminate throughout the animal causing a leukaemia-like disease called tropical theileriosis. Using deep RNAseq of T. annulata-infected B cells and macrophages we identify a set of microRNAs induced by infection, whose expression diminishes upon loss of the hyper-disseminating phenotype of virulent transformed macrophages. We describe how infection-induced upregulation of miR-126-5p ablates JIP-2 expression to release cytosolic JNK to translocate to the nucleus and trans-activate AP-1-driven transcription of mmp9 to promote tumour dissemination. In non-disseminating attenuated macrophages miR-126-5p levels drop, JIP-2 levels increase, JNK1 is retained in the cytosol leading to decreased c-Jun phosphorylation and dampened AP-1-driven mmp9 transcription. We show that variation in miR-126-5p levels depends on the tyrosine phosphorylation status of AGO2 that is regulated by Grb2-recruitment of PTP1B. In attenuated macrophages Grb2 levels drop resulting in less PTP1B recruitment, greater AGO2 phosphorylation, less miR-126-5p associated with AGO2 and a consequent rise in JIP-2 levels. Changes in miR-126-5p levels therefore, underpin both the virulent hyper-dissemination and the attenuated dissemination of T. annulata-infected macrophages.
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Malak Haidar, Zineb Rchiad, Hifzur Rahman Ansari, Fathia Ben-Rached, Shahin Tajeri, et al.. miR-126-5p by direct targeting of JNK- interacting protein-2 (JIP-2) plays a key role in Theileria-infected macrophage virulence. PLoS Pathogens, Public Library of Science, 2018, 14 (3), pp.e1006942. ⟨10.1371/journal.ppat.1006942⟩. ⟨inserm-02172086⟩

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