Stemness factor Mex3a times translation and protein trafficking to ensure robust differentiation of olfactory sensory neurons

During the switch from progenitor to differentiated cell, cellular physiology must change to accommodate increased translation and trafficking of membrane-bound proteins. We identify RNA-binding and E3 ubiquitin ligase Mex3a as a key driver of proper neuronal differentiation by regulating mRNA translation and trafficking of cell surface proteins in the context of Unfolded Protein Response (UPR) signaling. Loss of Mex3a in immature olfactory sensory neurons (OSNs) leads to defects in cilia structure, cell surface protein expression, and planar cell polarity in mature OSNs. Proteomics reveal a Mex3a-dependent decrease in proteins related to vesicle transport, lipid metabolism, and ribosome biogenesis. We identify RNA and ubiquitin targets of Mex3a and provide evidence that Mex3a may confer K27 ubiquitin linkage on substrates. Finally, modulating cellular levels of Mex3a changes the recruitment of translation factors Serbp1 and p-eEF2 to ribosomes with possible effects on translation. Our data reveal how a stemness factor regulates development post-transcriptionally and post-translationally to ensure robust differentiation. Highlights: Loss of stemness factor Mex3a in immature olfactory neurons leads to defects in mature olfactory neurons.Translation/Trafficking of cell surface proteins, cilia structure, and planar cell polarity are compromised in the absence of Mex3a.Mex3a may confer K27 ubiquitination on stress granule protein Serbp1 and ribosome protein Rps7.Mex3a levels are associated with Serbp1 and p-eEF2 recruitment to ribosomes.