Abstract
In metazoan cells, accumulation of misfolded proteins in the endoplasmic reticulum (ER) triggers the unfolded protein response (UPR) in which unconventional splicing of a precursor form of XBP1 (XBP1u) mRNA by an ER membrane protein, IRE1, results in the formation of mature XBP1s messenger RNA (mRNA). The XBP1s mRNA encodes a functional transcription factor that induces the expression of the ER resident molecular chaperones to alleviate the stressful situation. The nascent XBP1u peptide recruits the mRNA–ribosome–nascent chain (R-RNC) complex to the ER membrane. Yanagitani et al. (p. [586][1], published online 13 January; see the Perspective by [ Ron and Ito ][2]) now report that translation of XBP1u mRNA is transiently paused near the 3′ end of its open reading frame to stabilize the R-RNC complex. Mutational analysis of XBP1u revealed an evolutionarily conserved peptide module at the Cterminal region responsible for translational pausing, which was required for the efficient ER-targeting and splicing of the XBP1u mRNA. Thus, regulation of translational speed using a module embedded inside a protein promotes targeting of its mRNA for efficient splicing. [1]: /lookup/doi/10.1126/science.1197142 [2]: /lookup/doi/10.1126/science.1202075
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