A local translation program regulates centriole amplification in the airway epithelium

Abstract

AbstractBiogenesis of organelles requires targeting of a subset of proteins to specific subcellular domains by signal peptides or mechanisms controlling mRNA localization and local translation. How local distribution and translation of specific mRNAs for organelle biogenesis is achieved remains elusive and likely to be dependent on the cellular context. Here we identify Trinucleotide repeat containing-6a (Tnrc6a), a component of the miRNA pathway, distinctively localized to apical granules of differentiating airway multiciliated cells (MCCs) adjacent to centrioles. In spite of being enriched in TNRC6A and the miRNA-binding protein AGO2, they lack enzymes for mRNA degradation. Instead, we found these apical granules enriched in components of the mRNA translation machinery and newly synthesized proteins suggesting that they are specific hubs for target mRNA localization and local translation in MCCs. Consistent with this,Tnrc6aloss of function prevented formation of these granules and led to a broad reduction, rather than stabilization of miRNA targets. These included downregulation of key genes involved in ciliogenesis and was associated with defective multicilia formation both in vivo and in primary airway epithelial cultures. Similar analysis of Tnrc6a disruption in yolk sac showed stabilization of miRNA targets, highlighting the potential diversity of these mechanisms across organs.HighlightsTnrc6ais expressed in the lung selectively in differentiating multiciliated cells (MCC) adjacent to centrioles.TNRC6A localizes to apical granules containing AGO2, miRNAs and their targets, but lacking mRNA degradation enzymes.TNRC6A granules are enriched in components of the mRNA translation machinery and show evidence of concentrated newly-synthesized proteinsLoss ofTnrc6ain the lung leads to reduction, not stabilization of miRNA targets.Tnrc6ais required for efficient centriole amplification and multicilia formation.