An Ancient Family of RNA-Binding Proteins: Still Important

RNA-binding proteins are important modulators of mRNA stability, a crucial process that determines the ultimate cellular levels of mRNAs and their encoded proteins. The tristetraprolin (TTP) family of RNA-binding proteins appeared early in the evolution of eukaryotes, and has persisted in modern eukaryotes. The domain structures and biochemical functions of family members from widely divergent lineages are remarkably similar, but their mRNA 'targets' can be very different, even in closely related species. Recent gene knockout studies in species as distantly related as plants, flies, yeasts, and mice have demonstrated crucial roles for these proteins in a wide variety of physiological processes. Inflammatory and hematopoietic phenotypes in mice have suggested potential therapeutic approaches for analogous human disorders. Regulation of gene expression occurs at several stages, from transcriptional initiation to mRNA translation. Post-transcriptional control of gene expression by RNA-binding proteins plays an essential role in this process. TTP family members are defined by tandem CCCH zinc-finger domains that bind to AU-rich elements found in the 3′-untranslated regions of target mRNAs, and stimulate their turnover. TTP family members from evolutionarily distant species also contain a conserved C-terminal sequence that, in human TTP, can bind to the CCR4–NOT deadenylase complex through an interaction with the NOT1 subunit, providing a potential mechanism for the action of these proteins to destabilize mRNA. Gene knockout studies from organisms as distant as plants and mice demonstrate that these proteins regulate important physiological pathways that can differ between species.