Edc3 function in yeast and mammals is modulated by interaction with NAD-related compounds

The control of mRNA translation and degradation is mediated in part by a set of proteins that can inhibit translation and promote decapping, as well as function in the assembly of cytoplasmic mRNP granules referred to as processing bodies (P-bodies). The conserved enhancer of mRNA decapping 3 (Edc3) protein functions to promote both decapping and P-body assembly. Crystal structures of the YjeF_N domain in hEdc3 identified a putative binding site for a small molecule. Structure modeling of the human Edc3 Yjef_N along with other Yjef_N-containing proteins suggests that this molecule is related to NAD(H). We now show human Edc3 directly binds NADH. We also show that human and yeast Edc3 chemically modify NAD in vitro. Mutations that are predicted to disrupt the binding and/or hydrolysis of an NAD-related molecule by yeast and human Edc3 affect the control of mRNA degradation and/or P-body composition in vivo. This suggests that the interaction of Edc3 with an NAD-related molecule affects its function in the regulation of mRNA translation and degradation and provides a possible mechanism to couple the energetics of the cell to posttranscriptional control. Moreover, this provides a unique example of and lends strength to the postulated connection of metabolites, enzymes, and RNA.