A role for the ribosome-associated complex in activation of the IRE1 branch of UPR

The ubiquitous ribosome-associated complex (RAC) is a chaperone that spans ribosomes, making contacts near both the polypeptide exit tunnel and the decoding center, a position prime for sensing and coordinating translation and folding. Loss of RAC is known to result in growth defects and sensitization to translational and osmotic stresses. However, the physiological substrates of RAC and the mechanism(s) by which RAC is involved in responding to specific stresses in higher eukaryotes remain obscure. Data presented here uncover an essential function of mammalian RAC in the unfolded protein response (UPR). Knockdown of RAC sensitizes mammalian cells to ER stress and selectively interferes with IRE1 branch activation. Higher-order oligomerization of the IRE1a kinase/endoribonuclease depends upon RAC. These results reveal a surveillance function for RAC in the UPR: modulating IRE1a clustering as required for endonuclease activation and splicing of the substrate Xbp1 mRNA. Overall design: Ribosome profiling of XBP1 in the Thapsigargin-induced ER stress condition in HEK293 cells