Unspliced regulator

Although most RNA splicing occurs in the nucleus, HAC1 and XBP1 mRNAs are spliced in the cytoplasm during ER stress. On page 565, Yoshida et al. demonstrate that in the case of XBP1 both the unspliced and spliced RNAs produce functional proteins and together the proteins form a feedback system that controls the duration of the stress response.

When unfolded proteins accumulate in the ER, sensor proteins trigger expression of chaperones. One sensor, IRE1, is a membrane-bound RNase located in the ER membrane. IRE1 cleaves XBP1 RNA to produce an mRNA encoding a transcription factor. Although unspliced XBP1, (XBP1[U]), is translated, it is degraded immediately and previously had no known function.

With improved extraction techniques, Yoshida et al. found that XBP1(U) does accumulate in cells and shuttles between the nucleus and cytoplasm. Moreover, XBP1(U) bound to the spliced form of the protein, XBP1(S), and the binding appeared to accelerate degradation of XBP1(S).

During the initial phase of the stress response, IRE1 was highly active, and most of the XBP1 RNA was spliced, allowing XBP1(S) to stimulate transcription of chaperones. As the amount of unfolded protein decreased, so did IRE1 activity, and the amount of XBP1(U) increased relative to XBP1(S). With more XBP1(U) available to sop up the spliced protein, activation of chaperone transcription was rapidly reduced.

This system should respond rapidly as it is acting on a pool of preformed cytoplasmic RNA; by contrast, any change in nuclear splicing patterns must wait for new transcription to supply a substrate. With that advantage in mind, and noting the elaborate machinery used by the IRE1 system, the team speculates that there must be other RNA templates that use the system. Already, the HAC1 RNA is known to have similar regulation, but the team is on the hunt for more.