Figure 4.

Translational pausing and IRE1-mediated splicing of XBP1. To be poised for rapid splicing in response to the accumulation of unfolded proteins in the ER, unspliced XBP1u mRNA is tethered to the ER membrane by the paused ribosome–nascent chain complex. Pausing requires interactions of Leu246 and Trp256 in the nascent chain with the ribosome. The pause stabilizes the complex, favoring cleavage of XBP1u by IRE1. This causes a frameshift in the coding sequence of the spliced XBP1s mRNA, which precludes translation of Leu246 and Trp256 and relieves the pause. (Reprinted, with permission, from Ron and Ito 2011.)