1. Myles H. Thaler Center for AIDS & Human Retrovirus Research and Department of Microbiology, University of Virginia, Charlottesville, Virginia 22908, USA

Correspondence to: Marie-Louise Hammarskjöld¹ Correspondence and requests for materials should be addressed to M.-L.H. (Email: mh7g@virginia.edu).

Abstract

Alternative splicing is a key factor contributing to genetic diversity and evolution¹. Intron retention, one form of alternative splicing, is common in plants² but rare in higher eukaryotes^{3, 4, 5, 6, 7, 8}, because messenger RNAs with retained introns are subject to cellular restriction at the level of cytoplasmic export and expression^{9, 10}. Often, retention of internal introns restricts the export of these mRNAs and makes them the targets for degradation by the cellular nonsense-mediated decay machinery if they contain premature stop codons^{11, 12}. In fact, many of the database entries for complementary DNAs with retained introns represent them as artefacts that would not affect the proteome¹¹. Retroviruses are important model systems in studies of regulation of RNAs with retained introns, because their genomic and mRNAs contain one or more unspliced introns¹⁰. For example, Mason–Pfizer monkey virus overcomes cellular restrictions by using a cis-acting RNA element known as the constitutive transport element (CTE)¹³. The CTE interacts directly with the Tap protein (also known as nuclear RNA export factor 1, encoded by NXF1), which is thought to be a principal export receptor for cellular mRNA¹⁴, leading to the hypothesis that cellular mRNAs with retained introns use cellular CTE equivalents to overcome restrictions to their expression¹⁰. Here we show that the Tap gene contains a functional CTE in its alternatively spliced intron 10. Tap mRNA containing this intron is exported to the cytoplasm and is present in polyribosomes. A small Tap protein is encoded by this mRNA and can be detected in human and monkey cells. Our results indicate that Tap regulates expression of its own intron-containing RNA through a CTE-mediated mechanism. Thus, CTEs are likely to be important elements that facilitate efficient expression of mammalian mRNAs with retained introns.

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