Making ends meet: a role of RNA ligase RTCB in unfolded protein response

Abstract

The unfolded protein response (UPR) monitors the protein folding capacity of the endoplasmic reticulum. One of the UPR branches includes an unusual cytoplasmic splicing reaction leading to removal of an intron from an mRNA encoding a key UPR transcription factor. The cleavage step of the process is well characterized in both yeast and animals, but the animal enzyme responsible for exon ligation has remained a mystery. Recent reports, including a paper in this issue of The EMBO Journal, identify RTCB as the RNA ligase operating during UPR in mammals and C. elegans.

Figure 1. Processing of XBP1 mRNA during UPR

(A) Binding of unfolded proteins to the intra-lumenal domain (in orange) of IRE-1 causes its oligomerization and activation of the ribonuclease domain (in red). The IRE1 kinase domain, which is important for IRE1 regulation, is in blue. Cleavage and ligation of XBP1 mRNA is schematically shown below, with exons represented by thick and the intron by thin lines. (B) Chemistry of the RNA ligation step. The IRE1-mediated cleavage of pre-mRNA in the stem-loop border structures produces 2′,3′-cyclic phosphate and 5′-OH termini in both yeast and metazoa. In yeast, two exons are ligated via a 2′-phosphomonoester, 3′,5′-phosphodiester linkage, with the linking phosphate originating from the end of the downstream exon undergoing 5′-phosphorylation. The 2′-phosphate is removed from the final spliced product. In animals, RTCB catalyzes formation of a regular phosphodiester bond. The exon 3′-terminal cyclic phosphate and its fate during ligation reaction are marked in red.