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

• Published in: PLoS pathogens 2018-03, Vol.14 (3), p.e1006942
• Main Authors: Haidar, Malak, Rchiad, Zineb, Ansari, Hifzur Rahman, Ben-Rached, Fathia, Tajeri, Shahin, Latre De Late, Perle, Langsley, Gordon, Pain, Arnab
• Format: Article
• Language: English
• Subjects: Activator protein 1; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Argonaute 2 protein; Attenuation; Authorship; Biochemistry, Molecular Biology; Bioinformatics; Biology and Life Sciences; c-Jun protein; Cattle; Causes of; Cells, Cultured; Cytosol; Engineering; Environmental science; Funding; Gelatinase B; Gene expression; Genomics; Genotype & phenotype; Grb2 protein; Immunology; Infections; Kinases; Laboratories; Leukemia; Life Sciences; Lymphocytes B; Macrophages; Macrophages - metabolism; Macrophages - microbiology; MAP Kinase Kinase 4 - genetics; MAP Kinase Kinase 4 - metabolism; Medicine and Health Sciences; Microbiology and Parasitology; MicroRNA; MicroRNAs; MicroRNAs - genetics; miRNA; Nuclei; Pain; Parasites; Pathogens; Phenotypes; Phosphatase; Phosphorylation; Physical Sciences; Proteins; Recruitment; Research and Analysis Methods; Supervision; Theileria; Theileria annulata; Theileria annulata - pathogenicity; Theileriasis - genetics; Theileriasis - metabolism; Theileriasis - microbiology; Theileriosis; Transcription Factor AP-1 - genetics; Transcription Factor AP-1 - metabolism; Transcription factors; Tumors; Tyrosine; Virulence; Virulence - genetics
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1006942

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.