Hierarchical TAF1-dependent co-translational assembly of the basal transcription factor TFIID

Large heteromeric multiprotein complexes play pivotal roles at every step of gene expression in eukaryotic cells. Among them, the 20-subunits basal transcription factor TFIID nucleates RNA polymerase II preinitiation complex at gene promoters. Here, by combining systematic RNA-immunoprecipitation experiments, single-molecule imaging, proteomics and structure-function analyses, we show that TFIID is built using co-translational assembly. We discovered that all early steps of TFIID assembly, involving protein heterodimerization, happen during protein synthesis. Strikingly, we identify TAF1 – the largest protein in the complex – as a flexible scaffold subunit that co-translationally recruits preassembled TFIID submodules found populating the cytoplasm of cells. Consequently, TAF1 depletion leads to a cytoplasmic accumulation of TFIID building blocks. Altogether, our data suggest a multistep hierarchical model for TFIID biogenesis that culminates with the co-translational assembly on nascent TAF1 polypeptide, that works as a ‘driver’ subunit. We envision that this assembly strategy could be shared with other large heteromeric protein complexes.