Séminaire Département de Biologie - Dr. Clément CHAPAT

Wednesday, 22^nd of November 2017 at 14h00
Amphithéâtre SAUVY, Ecole polytechnique,    

Dr Clément CHAPAT
Goodman Cancer Research Center, Department of Biochemistry,
McGill University, Montreal, Quebec, Canada           

miRNAs are important components of gene regulatory networks and affect all aspects of cell biology by controlling the stability and translation efficiency of their target mRNAs. The CCR4-NOT complex effects miRNA-mediated silencing at least in part through interactions with DDX6 and 4E-T (eIF4E-Transporter) proteins. Through screening for protein interactions in cells via the BioID method, we recently identified the cap-binding eIF4E-Homologous Protein 4EHP as a component of the CCR4-NOT/DDX6/4E-T axis. We demonstrated that the cap-binding activity of 4EHP contributes to the translational silencing by miRNAs through the CCR4-NOT complex, and proposed a model wherein the 4E-T/4EHP interaction engenders a closed loop mRNA conformation that blocks translational initiation of miRNA targets. An additional layer of complexity in understanding the exact mechanism of 4EHP action stems from the interaction of 4EHP with the GRB10-interacting GYF (glycine-tyrosine-phenylalanine domain) proteins, GIGYF1 and 2. The GIGYF1/2-4EHP complex has been characterized as a translational repressor, notably as a cofactor of tristetraprolin and GW182 proteins. Here, we show that the GIGYF1/2 proteins are associated with the mRNA decay machinery and interact with silencing factors including the CCR4-NOT complex. In functional assays, we provide evidence that GIGYF1/2 block the translation of mRNAs in a deadenylation-independent manner. Importantly, we demonstrate that mutation of the GYF residues relieves repression of GIGYF1/2-bound mRNAs, and we reveal that GIGYF1/2 do not need to interact with 4EHP to engender mRNA silencing. Altogether, our data suggest that the GIGYF1/2 proteins nucleate a complex network of mRNA silencing factor interactions which can be implicated in various post-transcriptional regulatory pathways.

Lieu(x) : Ecole Polytechnique, Amphithéâtre  SAUVY

Contact : Marc Graille