Fig. 9. GNL3L inhibits the transcriptional activities of ERR family genes by coactivator competition. Our data reveal a novel mechanism that regulates the activity of ERR family genes by the nucleolar GTP-binding protein GNL3L. GNL3L decreases the transcriptional activity of ERR proteins. This event takes place in the nucleoplasm and does not require the nucleolar localization of GNL3L. The interaction between GNL3L and ERR displaces coactivators such as SRC1 and SRC2 from the ERR complex. The SRC-depleted ERR protein binds DNA without GNL3L, resulting in transcriptional inhibition. In this model, the nucleolar accumulation of GNL3L does not appear to affect its ability to suppress the transcriptional function of ERR proteins (grey arrows). Protein domains of GNL3L and ERR are: B, basic domain; C1 and C2, coiled-coil domain-1 and -2; G, GTP-binding domain; I, intermediate domain; AF1 and AF2, activation function 1 and 2; DBD, DNA-binding domain; LBD, ligand-binding domain.