On 2014 Oct 29, Benoit Kornmann commented:

The unfolded protein response (UPR) is a conserved pathway that senses stress in the endoplasmic reticulum (ER) and responds to it by eliciting a transcriptional response. Mechanistically, when the stress sensor IRE1 is activated by the accumulation of unfolded proteins in the ER, its cytosolic RNAse domain cleaves the messenger of a transcription factor (Xbp1 in mammals, Hac1 in yeast) at two precise positions, removing an inhibitory intron. The 5' and the 3' parts of the messenger are then re-ligated together, to encode a functional transcription factor that takes part in the response. While the ligase involved in the last processing step was known in yeast, it evaded identification for years in mammals.

Here, the mammalian ligase is identified using a clever trick. A synthetic construct consisting of a Cre recombinase fused to Xbp1 is not expressed in normal conditions, but upon ER stress, Xbp1 is spliced and Cre recombinase is produced. The induction of the recombinase can be easily monitored using a Cre-induced proapoptotic factor, which kills the cells. Using this synthetic circuit, the authors screen a lentiviral RNA interference (RNAi) library and identify hits that fail to induce Cre upon acute ER stress, by simply scoring for survival. They identify the ligase RtcB, which, as with the yeast UPR ligase Trl1, is also involved in tRNA splicing.

On 2014 Oct 29, Benoit Kornmann commented:

The unfolded protein response (UPR) is a conserved pathway that senses stress in the endoplasmic reticulum (ER) and responds to it by eliciting a transcriptional response. Mechanistically, when the stress sensor IRE1 is activated by the accumulation of unfolded proteins in the ER, its cytosolic RNAse domain cleaves the messenger of a transcription factor (Xbp1 in mammals, Hac1 in yeast) at two precise positions, removing an inhibitory intron. The 5' and the 3' parts of the messenger are then re-ligated together, to encode a functional transcription factor that takes part in the response. While the ligase involved in the last processing step was known in yeast, it evaded identification for years in mammals.

Here, the mammalian ligase is identified using a clever trick. A synthetic construct consisting of a Cre recombinase fused to Xbp1 is not expressed in normal conditions, but upon ER stress, Xbp1 is spliced and Cre recombinase is produced. The induction of the recombinase can be easily monitored using a Cre-induced proapoptotic factor, which kills the cells. Using this synthetic circuit, the authors screen a lentiviral RNA interference (RNAi) library and identify hits that fail to induce Cre upon acute ER stress, by simply scoring for survival. They identify the ligase RtcB, which, as with the yeast UPR ligase Trl1, is also involved in tRNA splicing.