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

Malak Haidar 1, 2, 3 Zineb Rchiad 1, 2, 3 Hifzur Rahman Ansari 1 Fathia Ben-Rached 1 Shahin Tajeri 2, 3 Perle de Late 2, 3 Gordon Langsley 2, 3, * Arnab Pain 1, 4, *
* Corresponding author
1 Pathogen Genomics Laboratory [Thuwal, Arabie saoudite]
2 IC UM3 (UMR 8104 / U1016) - Institut Cochin
3 Laboratoire de Biologie Cellulaire Comparative des Apicomplexes [Paris]
4 GSZ - Global Station for Zoonosis Control [Sapporo, Japon]
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.
Document type :
Journal articles
Complete list of metadatas

Cited literature [60 references]  Display  Hide  Download
https://www.hal.inserm.fr/inserm-02172086
Contributor : Myriam Bodescot <>
Submitted on : Wednesday, July 3, 2019 - 2:20:53 PM
Last modification on : Friday, July 5, 2019 - 1:18:24 AM

File

journal.ppat.1006942.pdf
Publication funded by an institution

Identifiers

Collections

CNRS | UNIV-PARIS5 | USPC

Citation

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⟩

Export

BibTeX TEI DC DCterms EndNote

Share

Metrics

Record views

84

Files downloads

71

Contact

CCSD