mRNA “quality control” can sometimes be ignored — when the cell needs to respond immediately to STRESS signals

Even though the model system here [attached] is Yeast Culture, cells (everywhere, even among individual cells of the same cancer, or bacteria in an infection or in the gastrointestinal tract) “grow well and are happy” –– only in a remarkably narrow range of physiological conditions. “Surviving extreme conditions” is a property that requires the instantaneous expression of “chaperones” that help to overcome stressful situations. To ensure the preferential synthesis of these heat-shock proteins (HSPs), cells inhibit transcription, pre-mRNA processing, and nuclear export of nonheat-shock transcripts, whereas stress-specific mRNAs are exclusively exported and translated.

This area of research (comparing normally-folded proteins with misfolded proteins) was championed by my friend and colleague, the late Susan Lindquist.

How cells manage this selective retention of regular transcripts and the simultaneous rapid export of heatshock mRNAs –– remains largely unknown.

In Saccharomyces cerevisiae (brewers’s yeast), the shuttling-RNA adaptor proteins –– Npl3, Gbp2, Hrb1 and Nab2 –– are loaded co-transcriptionally onto growing pre-mRNAs. For nuclear export, these adaptor proteins recruit the export-receptor heterodimer, Mex67–Mtr2 (called TAP–p15 in humans). In the attached paper, authors show that cellular stress induces the dissociation of Mex67, and its adaptor proteins, from regular mRNAs in order to prevent general mRNA export. At the same time, heat-shock mRNAs are rapidly exported in association with Mex67 –– without the need for adapters. The immediate co-transcriptional loading of Mex67 onto heat-shock mRNAs involves Hsf1, a yeast heat-shock transcription factor that binds to HSP promoter elements in stress-responsive genes.

An important difference, between these two possible export modes, is that adaptor-protein-bound mRNAs undergo Quality Control, whereas stress-specific transcripts do not.  In fact, regular mRNAs are converted into uncontrolled stress-responsive transcripts –– if they are expressed under the control of a heat-shock promoter; this suggests that, whether or not an mRNA undergoes quality control, is encrypted therein. Under normal conditions, Mex67 adaptor proteins are recruited for RNA surveillance, with only quality-controlled mRNAs allowed to associate with Mex67 and leave the nucleus.

Hence, this fascinating study indicates that, at the expense of error-free mRNA formation, HSP mRNAs are exported and translated without delay –– allowing cells to survive quicly under extreme situations.

Nature  Dec 2o16; 540: 593–596

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