The CCR4–NOT complex: a multifaceted sensor of molecular signals instructing eukaryotic mRNA translation and stability

The CCR4-NOT complex is a multi-subunit assembly found in all eukaryotic cells. Yet, its composition varies across organisms, with a universally conserved core enriched by lineage-specific subunits. Further, heterogeneity results from the occurrence of paralogous proteins, substoichiometric subunits, transient partners, and protein isoforms. Altogether, multiple CCR4-NOT complexes exist, and some even coexist within a single cell. The CCR4-NOT complex is an essential actor of gene expression through its roles in messenger RNA (mRNA) deadenylation, decay, and translation. Over time, support for the originally proposed role of the CCR4-NOT complex in transcription has been waning. Consistent with a role in post-transcriptional regulation, ribosomes appear to be major partners of the CCR4-NOT complex to coordinate translation and mRNA decay. Further, the CCR4-NOT complex is at the center of a network involving RNA-binding proteins and ubiquitin ligases, as well as factors of currently unknown function. Structural and functional analyses indicate that the CCR4-NOT complex integrates different levels of information present in mRNAs to control their stability and translation, thereby contributing to diverse functions including intricate processes such as human brain or pancreas development. It is thus not surprising that genetic alteration of this essential cellular machine, or impairment of its activity by pathogens, contributes to human diseases.