Abstract
The ubiquitous ribosome-associated complex (RAC) is a chaperone that spans ribosomes, making contact near both the polypeptide exit tunnel and the decoding center, a position prime for coordination of translation and folding. Loss of RAC results in growth defects and sensitization to translational stress. The mechanism of RAC in responding to specific stresses remains obscure. Data presented here uncover an essential function of mammalian RAC in the unfolded protein response (UPR), coupling the inositol-requiring protein 1α (IRE1α) branch to translation. Knockdown of RAC sensitizes mammalian cells to ER stress by selectively interfering with IRE1α activation. Higher-order oligomerization of IRE1α kinase/endoribonuclease and accurate ribosome stalling of Xbp1 mRNA, as required for IRE1α mediated Xbp1 mRNA splicing activity, depends upon RAC. These results reveal a surveillance function for RAC on the ribosomes: modulating IRE1α clustering and the fitness of Xbp1 mRNA splicing in coordination with translation.
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