NAC regulates metabolism and cell fate in intestinal stem cells

mRNA translation is a highly dynamic process that has been shown to modulate cell adaptation to stress conditions. Upon ribosome impairment, ZAKα affects the metabolic profile of intestinal cells, however the mechanism by which this is promoted is still unclear. Here, we identified the nascent polypeptide-associated complex (NAC) as a central player in the metabolic regulation triggered by ribosome impairment. Furthermore, we show that NAC is essential for the survival of the highly oxidative phosphorylation (OXPHOS) reliant intestinal stem cells (ISCs), being translationally regulated itself. NAC interacts with the ribosome and promotes the transport of the translation machinery and newly-formed peptides to the proximity of the mitochondria, allowing the import of proteins essential for processes such as OXPHOS. Upon translation stress, NAC is inhibited through an interaction with ZAKα, leading to the downregulation of OXPHOS. Overall, our findings unveil that NAC is a central player in translation-mediated metabolic regulation in intestinal cells. Ribo-seq and RNAseq based identification of translationally regulated genes in intestinal stem cells and their essentiality analysis with a CRISPR drop-out screen