Eukaryotes have two types of spliceosomes, comprised of either major (U1, U2, U4, U5, U6) or minor (U11, U12, U4atac, U6atac; <1%) snRNPs. The high conservation of minor introns, typically one amidst many major introns in several hundred genes, despite their poor splicing, has been a long-standing enigma. Here, we discovered that the low abundance minor spliceosome’s catalytic snRNP, U6atac, is strikingly unstable (t½<2 hr). We show that U6atac level depends on both RNA polymerases II and III and can be rapidly increased by cell stress-activated kinase p38MAPK, which stabilizes it, enhancing mRNA expression of hundreds of minor intron-containing genes that are otherwise suppressed by limiting U6atac. Furthermore, p38MAPK-dependent U6atac modulation can control minor intron-containing tumor suppressor PTEN expression and cytokine production. We propose that minor introns are embedded molecular switches regulated by U6atac abundance, providing a novel post-transcriptional gene expression mechanism and a rationale for the minor spliceosome’s evolutionary conservation.
The central dogma of biology states that genetic material, DNA, is transcribed into RNA, which is then translated into proteins. However, the genes of many organisms have stretches of non-coding DNA that interrupt the sequences that code for protein. These non-coding sequences, which are called introns, must be removed, and the remaining sequences—which are called exons—must then be joined together to produce a messenger RNA (mRNA) transcript that is ready to be translated into protein.
The process of removing the introns and joining the exons is called splicing, and it is carried out by a molecular machine called the spliceosome. However, in addition to containing typical (‘major’) introns, several hundred human genes also contain a single ‘minor’ intron, and a minor spliceosome is needed to remove it. Minor introns occur in many highly conserved genes, but they are often inefficiently spliced. This means that the resulting mRNA transcripts may not be translated into proteins—which is puzzling given that these proteins perform important roles within the cell.
The major and minor spliceosomes are composed of proteins and small non-coding RNA molecules (which, as their name suggests, are never translated in cells). Now Younis et al. shed new light on the minor spliceosome by showing that a small non-coding RNA molecule known as U6atac, which catalyzes the removal of introns by the minor spliceosome, is highly unstable in human cells. This means that U6atac is a limiting factor for the splicing of minor introns—a process that is already limited by the very low abundance of the minor spliceosome under normal conditions. However, Younis et al. found that this bottleneck could be relieved by halting the degradation of U6atac. Experiments showed that U6atac can be stabilized by a key signaling molecule, a protein kinase (called p38MAPK), which is activated in response to stress. The resulting higher levels of U6atac promoted splicing of the introns in its target mRNA transcripts, and also modulated various signaling pathways in the cells.
Together, these results imply that the minor spliceosome is used as a valve that can help cells to adapt to stress and other changes. Moreover, by helping to translate mRNA transcripts that are already present in cells, it enables proteins to be produced rapidly in response to stress, bypassing the need for a fresh round of transcription.