Smg also regulates mRNA translation through a separate mechanism involving an NVP-BKM120 interaction with the eIF4E-binding protein Cup. Cup binds to the mRNA cap binding protein eIF4E through a canonical eIF4E-binding motif. Cap-dependent translation initiation involves eIF4E recruiting eIF4G to an mRNA, which indirectly mediates recruitment of the 40S ribosome. eIF4G also interacts with eIF4E through an eIF4E-binding motif and thus recruitment of Cup to an mRNA inhibits translation by blocking the eIF4E/ eIF4G interaction. The role of Cup in Smg function led us to speculate that Vts1p might also regulate target mRNAs through an eIF4E-binding protein. While there is no Cup homolog in yeast, two eIF4Ebinding proteins, Caf20p and Eap1p, have been identified. In addition, global genetic analysis revealed synthetically lethal interactions between Eap1p and two deadenylase components, Ccr4p and Pop2p, suggesting a functional relationship, either direct or indirect, among the gene products. This genetic interaction combined with the role of the Ccr4pPop2p-Not deadenylase in Vts1p-mediated regulation prompted us to test if Eap1p might function with Vts1p to regulate target mRNAs. Using two different Vts1p target mRNAs we demonstrate that Eap1p is required for efficient Vts1p-mediated transcript degradation. Eap1p does not stimulate deadenylation but is instead required for efficient removal of the 59 cap. In addition, Eap1p-mediated stimulation of transcript decay requires binding to eIF4E. We also find that Eap1p biochemically interacts with Vts1p and is able to mediate an indirect interaction between Vts1p and eIF4E. Taken together these data suggest a model whereby the Vts1p/Eap1p/eIF4E complex stimulates transcript decapping. Here we demonstrate a role for Eap1p in Vts1p-mediated mRNA decay. The ability of Eap1p to interact with the cap binding protein eIF4E is required for this function and, consistent with its proximity to the 59 cap, Eap1p stimulates mRNA decapping. While Eap1p is required for efficient decay of a reporter mRNA bearing wild-type SREs, it is not required for degradation of a reporter bearing mutated non-functional SREs. This suggests a specific role for Eap1p in the degradation of Vts1p target transcripts. In addition, we show that Vts1p interacts with Eap1p and that Eap1p is able to mediate an indirect interaction between Vts1p and eIF4E. Taken together these data suggest a model whereby recruitment of Eap1p to target transcripts, through its interaction with Vts1p, stimulates decapping via binding to eIF4E. Interestingly, another RNA binding protein, Puf5p, also functions with Eap1p to enchance the decapping of its target mRNAs. Alternatively, since the poly tail is known to stimulate translation, Vts1p-mediated deadenylation of target mRNAs could simultaneously repress translation and induce transcript decay; if so, the two processes would not be separable. A lack of a role for Eap1p in translational repression of Vts1p target mRNAs is consistent with the fact that a genome-wide survey of mRNAs that are translationally regulated by Eap1p show no statistically significant overlap with mRNAs that are bound by Vts1p. Thus the pool of Eap1p target mRNAs that are translationally regulated are distinct from the pool of Vts1p target mRNAs that are degraded. Since a poly tail is required for mRNA translation, perhaps Vts1p-mediated deadenylation represses mRNA translation to the point where Eap1p can no longer augment this effect.