microRNA-mediated gene silencing is enacted through the recruitment effector proteins that promote the translational repression or the degradation of mRNA targets. Concerted proteomic surveys on microRNA effector proteins identified the uncharacterized GYF-domain encoding protein, GYF-1. A reciprocal proteomic survey confirmed association with microRNA-mediated silencing components but also identified a robust interaction with IFE-4, the ortholog of the eIF4E-homologous protein 4EHP, which competes for EIF4E binding to 5'-cap structure. Loss of
gyf-1 leads to partially penetrant embryonic lethality, and to strict synthetic lethality with hypomorphic alleles of the
let-7 miRNA at the L4-to-adult transition. This latter genetic function can be largely but not completely attributed to
ife-4. Recruitment of GYF-1 to mRNA reporters in a cell free embryonic system leads to potent translation repression without affecting the poly(A) tail nor impinging on mRNA stability. Our findings reveal that the GYF-1/IFE-4 complex plays an important part in
let-7 functions by repressing the translation of mRNAs. Keywords: microRNA,
let-7, translation repression, protein-protein interaction, cap-binding protein.