Messenger RNA export from the nucleus: a series of molecular wardrobe changes

Abstract

The advent of the nucleus during the evolutionary development of the eukaryotic cell necessitated the development of a transport system to convey messenger RNA (mRNA) from the site of transcription in the nucleus to ribosomes in the cytoplasm. In this review, we highlight components of each step in mRNA biogenesis, from transcription to processing, that are coupled with mRNA export from the nucleus. We also review the mechanism by which proteins from one step in the mRNA assembly line are replaced by those required for the next. These 'molecular wardrobe changes' appear to be key steps in facilitating the rapid and efficient nuclear export of mRNA transcripts.

Figure 1

Schematics illustrating possible mechanisms for recruitment of the S. cerevisiae mRNA export receptor, Mex67, to mRNA transcripts are shown. A) ‘Classical’ model of Mex67 recruitment. The principle mRNA export heterodimer, Mex67:Mtr2, is recruited via direct interactions with Yra1 in a Sub2- and THO complex-dependent manner. THO complex members are initially deposited upon nascent transcripts via interactions with the C-terminal domain (CTD) of RNA polymerase II (RNA Pol II). Following THO deposition, Sub2 and Yra1 are recruited to the transcript. Finally, the heterodimeric complex of Mex67:Mtr2 is recruited via interactions between Yra1 and Mex67. Binding of Mex67 to Yra1 displaces Sub2. B) Sub2/Yra1-independent recruitment of Mex67. The heterodimeric export receptor, Mex67:Mtr2, can also be recruited to mRNA transcripts via direct interactions with both components of the THO complex, Hpr1, and the RNA-binding protein, Npl3. C) Revised ‘classical’ model of Mex67 recruitment. Mex67:Mtr2 is recruited to mRNA transcripts via interactions with 3′-end processing components. Although initial studies (5,15) showed that Yra1 was recruited to transcripts directly via THO components and Sub2, more recent data suggest a revised model where Yra1 is initially recruited to the mRNA transcript via interactions with the 3′-end processing factor, Pcf11 (19) and subsequently transferred to the TREX complex via an interaction with Sub2. Yra1 then recruits Mex67 and transcripts are exported.

Figure 2

A timeline for the molecular displacements that occur in the course of mRNA export. In S. cerevisiae, adaptor proteins responsible for the recruitment of mRNA export receptors are deposited upon transcripts (denoted by black curved lines above the large directional arrow) during transcription and processing, coupling these processes to mRNA export. During transcription, components of the THO complex are initially deposited on the nascent transcript. Other processing factors and RNA-binding proteins, such as Hrp1, Npl3, Sub2, Yra1 and Nab2 are subsequently recruited to the maturing transcript through a combination of interactions with THO components, the C-terminal domain of RNA polymerase II, and other mechanisms. The principle yeast mRNA export receptor heterodimer, Mex67:Mtr2, is subsequently recruited via interactions with adaptor proteins. Recruitment of Mex67:Mtr2 displaces Sub2 (denoted by blacked curved lines below the large directional arrow), eventually Yra1 is also displaced from the mRNA transcript, and the mRNP exits the nucleus through the nuclear pore complex. Once in the cytoplasm, the Dbp5 helicase remodels the mRNP, displacing export factors, such as Mex67 and Nab2, and subsequently allowing translation factors to bind to the transcript. As both Npl3 and Hrp1 associate with polyribosomes, the mechanism by which these proteins dissociate from the transcript is unclear (represented by white dashed lines below the large directional arrow). The mechanism and compartment of THO displacement also remains unclear, as the hTHO components shuttle between the nucleus and the cytoplasm, but shuttling of S. cerevisiae THO components has not been reported