Direct monitoring of unfolded nascent polypeptides by the CCR4-NOT complex contributes to protein quality control through selective mRNA deadenylation and decay

Accumulation of aberrant and unfolded proteins induce cellular stresses and contributes in human to diseases and aging. Several cellular pathways combat the formation of these deleterious molecules. Recently, processes limiting the production of unwanted polypeptides through the co-translational degradation of their messenger RNAs (mRNAs) have been identified but remain poorly understood. In Saccharomyces cerevisiae, Caf130 was proposed to regulate the levels of mRNAs encoding some ribosomal proteins, principally Rpl4, when they do not fold properly. We report the functional and structural characterization this process. Biochemical purifications, interaction assays, and in vivo analyses combined with Alphafold modelling define the organization and function of the Caf130 module of the CCR4-NOT complex and associated factors that mediate this process. Our data reveal the critical role of different forms of the Nascent protein Associated Complex (NAC) to dock the CCR4-NOT complex onto translating ribosomes. The CCR4-NOT complex directly recognizes some nascent unfolded proteins emerging from the ribosome tunnel triggering deadenylation of the mRNAs encoding them. Our data further reveal unsuspected evolutionary and functional similarities between yeast and mammalian proteins involved in the quality control of nascent proteins through mRNA degradation. Altogether, our data indicate the existence of a conserved machinery contributing to protein quality control by triggering the decay of mRNAs encoding deleterious polypeptides in eukaryotes.