Mixed Messages: Dynamic and Compositional Heterogeneity of Nuclear Messenger Ribonucleoprotein (mRNP) Complexes

Keywords: ALYREF, gene expression, mRNA, mRNP, RBP, RNA‐binding protein, Saccharomyces cerevisiae , THO, TREX, Yra1

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BOX 1. mRNP Nuclear Processing and Export Factors.

Cap binding proteins.

Nascent transcription by RNAPII leads to the recruitment of the 5′ capping enzyme and formation of the m⁷G cap structure on mRNA (Ramanathan et al. 2016). This modification results in the recruitment of the nuclear cap‐binding complex (CBC), which is composed of Cbp80 and Cbp20 in yeast and NCBP1 and NCBP2 in humans (Rambout and Maquat 2020). Of these, Cbp20/NCBP2 directly binds to the 5′ cap, while Cbp80/NCBP1 supports the interaction. CBC has a crucial role in the subsequent mRNA biogenesis steps, including transcription elongation, splicing, and 3′ end processing, by mediating interactions with various regulatory factors involved in these processes (Rambout and Maquat 2020). CBC association also facilitates the recruitment of RBPs linked to the nuclear mRNA export, underscoring its important role in mRNP packaging (Cheng et al. 2006; Clarke et al. 2024; Sen et al. 2019; Viphakone et al. 2019; Wechsler et al. 2025). The binding of CBC on the 5′ cap is also crucial to the fidelity and quality control of capping, with an interaction between Cbp80 and a core nuclear RBP component, Npl3, which, in the case of improper capping, triggers transcript degradation (Klama et al. 2022).

In addition to CBC, the cytoplasmic cap binding protein eIF4E is involved in nuclear mRNA processing and export (Mars et al. 2024). eIF4E is known to shuttle between the nucleus and cytoplasm, with significant amounts detected in the nuclei of various species, including yeast (Lang et al. 1994) and human (Cohen et al. 2001; Iborra et al. 2001). In mammals, eIF4E is imported into the nucleus by importin 8 (Volpon et al. 2016) and is involved in gene selective mRNA export. Specifically, eIF4E recognizes the 5' cap of nuclear mRNAs which have an eIF4E sensitivity element (4E‐SE), composed of a specific RNA stem‐loop pair, typically contained at the 3'UTR (Culjkovic et al. 2005). 4E‐SE is recognized by LRPPRC, and the interaction with eIF4E stabilizes these RBPs on target mRNPs (Topisirovic et al. 2009; Volpon et al. 2017). Unlike the conventional mRNA export pathway, eIF4E‐dependent export is mediated by CRM1, an export receptor commonly associated with the nuclear export of proteins, snRNAs, and rRNAs, through its interaction with LRPPRC (Culjkovic et al. 2006; Volpon et al. 2017).

Serine/Arginine‐rich (SR) proteins.

Human SR proteins are a class of RBPs with roles in nuclear mRNA processing, most notably an essential role in splicing, with some shuttling SR proteins also implicated in regulating nuclear export and translation in the cytoplasm (Howard and Sanford 2015; Jeong 2017; Wegener and Müller‐McNicoll 2019). These proteins are characterized by the presence of an RS domain enriched for serine and arginine residues and one or two RNA recognition motifs (RRMs). In S. cerevisiae , there are three "SR‐like" proteins (Npl3, Hrb1, Gbp2) with similarly documented nuclear roles in splicing and quality control of mRNA processing.

The yeast SR‐like protein, Npl3, is one of the most abundant nuclear RBPs with roles in mRNA biogenesis and export. Npl3 is recruited to the transcription site through the interaction with phosphorylated RNAPII C‐terminal domain (CTD) (Dermody et al. 2008; Gupta et al. 2023). Mutations disrupting Npl3 RNA binding impair recruitment and stability of the other nuclear mRNP components, highlighting the crucial role of Npl3 in mRNP assembly and organization (Keil et al. 2023). Similar to mammalian SR‐proteins, Npl3 is also involved in splicing (Kress et al. 2008; Sandhu et al. 2021), with a role in multiple steps of spliceosome function (e.g., U1 snRNP dissociation mediated by DEAD‐box helicase Prp28 (Yeh et al. 2021) and U2/U6 snRNAs duplex formation of B^act complex (Moursy et al. 2023)). The other SR‐like proteins encoded in yeast, Gbp2 and Hrb1, are involved in quality control to ensure the export of properly spliced mRNAs (Hackmann et al. 2014). These SR‐like proteins are recruited to the mRNA during the late step of the splicing and sort the mRNA for export or degradation depending on the status of intron removal. All three of these SR‐like proteins act as adaptor proteins for the mRNA export receptor Mex67‐Mtr2 to facilitate export (Gilbert and Guthrie 2004; Hackmann et al. 2014).

In mammals, a total of 12 SR proteins are encoded, referred to as serine/arginine‐rich splicing factors (SRSF) 1 to 12 (Wegener and Müller‐McNicoll 2019). CLIP‐seq analysis to identify SRSFs' target mRNAs and their binding sites revealed that SRSFs occupy most of the exons of protein‐coding genes. Furthermore, SRSFs bound RNAs also include exon‐exon junction reads, indicating that SRSFs remain associated with mRNPs even after completion of the splicing and serve as organizers of nuclear mRNPs (Müller‐McNicoll et al. 2016). In line with this observation, there are many reports that indicate SRSFs function in post‐splicing, including mRNA nuclear export and translation control (reviewed in Wegener and Müller‐McNicoll (2019)). Similar to yeast SR‐like proteins, SRSFs serve as adaptor proteins for the mRNA export receptor NXF1‐NXT1 in mammals (Hargous et al. 2006; Lai and Tarn 2004; Tintaru et al. 2007).

Exon‐Junction complex (EJC).

During splicing, the exon junction complex (EJC) is deposited 20–24 nt upstream of the exon‐exon junction as a marker of splicing completion (Schlautmann and Gehring 2020). EJC is composed of three core components, eIF4AIII, RBM8A, and MAGOH. Splicing‐dependent EJC assembly and loading to the exon‐exon junction is mediated through the physical interaction between a spliceosome component, CWC22, and eIF4AIII (Alexandrov et al. 2012; Barbosa et al. 2012; Steckelberg et al. 2012). Once assembled, the EJC core remains associated with the mRNA until the pioneer round of translation in the cytoplasm (Schlautmann and Gehring 2020). Persistent EJC binding to the mRNA is mediated by the RBM8A‐MAGOH heterodimer that locks eIF4AIII, a DEAD‐box ATPase, on the mRNA (Andersen et al. 2006; Bono et al. 2006). Once associated with an mRNA, the EJC core acts as an interaction platform for a variety of factors to direct events that include mRNA export and nonsense‐mediated decay (NMD) (Hug et al. 2016; Woodward et al. 2017). Purification of EJC‐bound mRNPs from human cells demonstrated that the EJC forms super‐assemblies on the mRNA that are important for the organization of the compacted higher‐order structure of the nuclear mRNPs (G. Singh et al. 2012).

THO/TRanscription‐EXport (TREX) Complex.

TREX is an evolutionarily conserved complex composed of the THO complex and other associated factors with roles in genomic stability, transcription, and export (Luna et al. 2019). The THO complex in yeast is composed of Tho2, Hpr1, Mft1, Thp2, and Tex1 (Luna et al. 2012) that is recruited via interaction with transcription machinery, including phosphorylated CTD of RNAPII itself and/or Prp19 complex (Chanarat et al. 2011; Henke‐Schulz et al. 2024; Meinel et al. 2013). Recruitment of THO is particularly important for highly expressed, GC‐rich, and long genes, as deletion of THO components diminishes the expression level of these genes (Gómez‐González et al. 2011). The THO complex further acts as an interaction platform for factors in mRNPs, which includes the DEAD‐box RNA helicase Sub2, mRNA export adaptor protein Yra1, and SR‐like proteins, Gbp2 and Hrb1 (Hurt et al. 2004; Sträßer et al. 2002). Since these associated RBPs are involved in mRNA export, THO in complex with Sub2 and Yra1 is referred to as the TRanscription and EXport (TREX) complex. Yra1 as an adaptor for the mRNA export receptor Mex67‐Mtr2 is essential for mRNA transport through the NPC (Strässer et al. 2000; Strässer and Hurt 2000; Stutz et al. 2000). Yra1 has a paralogous gene Yra2 that, when overexpressed, can complement the lethality of YRA1 gene deletion (Zenklusen et al. 2001). Recently, another RBP (Yhs7/YHR127W) has been identified in THO complex‐bound mRNPs with some structural and functional similarity to Yra1, with Yra2 sharing positively charged IDRs and RNA annealing activity (Bonneau et al. 2023), but lacking the UAP56 binding motif observed in Yra1/ALYREF. Structural analysis of recombinant THO complex in yeast has revealed a homodimer with two binding sites for Sub2 and Yra1 (Peña et al. 2012; Schuller et al. 2020; Xie et al. 2021). Transcriptome‐wide analysis of RBP binding has further shown that both Sub2 and Yra1 associate more frequently with longer gene transcripts (Baejen et al. 2014), suggesting an increased necessity for these proteins on mRNAs of certain features, indicative of gene‐dependent mRNP architectures.

In addition to the THO/TREX complex acting in transcription and mRNA export, the complex plays a role in preventing DNA–RNA hybrids, known as R‐loops (Huertas and Aguilera 2003). R‐loops are harmful nucleic acid structures that cause DNA double‐strand breaks (García‐Muse and Aguilera 2019). It is hypothesized that THO complex‐mediated mRNP organization prevents mRNA from annealing to the single‐stranded DNA generated during transcription (Luna et al. 2024). In line with this concept, many RBPs related to mRNA biogenesis and export are also identified as R‐loop preventing factors (Luna et al. 2024). For example, the RBP Tho1 was identified as both a multi‐copy suppressor of the R‐loop‐mediated genome instability phenotype and a nuclear export defect caused by the deletion of the THO complex component, HPR1 (Jimeno et al. 2006; Piruat and Aguilera 1998). This suggests the multiple functions attributed to THO/TREX through the analysis of mutants may be the result of inefficient mRNP packaging, which can be overcome by the function of other packaging factors.

The THO complex in mammals is a tetramer of a six‐subunit complex that includes THOC1, THOC2, THOC3, THOC5, THOC6, and THOC7 (Pühringer et al. 2020). The yeast Sub2 DEAD‐box ATPase has two paralogs encoded in mammals, UAP56 and URH49 (also referred to as DDX39B and DDX39A) (Pryor et al. 2004). The homolog of yeast Yra1, ALYREF, engages the TREX complex via interaction with UAP56 and is recruited to transcripts co‐transcriptionally via the CBC component NCBP1 (Cheng et al. 2006). ALYREF further mediates interaction between TREX and EJC, supporting the organization of compacted nuclear mRNPs (Gromadzka et al. 2016; Pacheco‐Fiallos et al. 2023; Viphakone et al. 2019). In mammals, ALYREF knockdown shows only a modest mRNA export defect compared to NXF1 depletion (Hautbergue et al. 2009; Katahira et al. 2009), suggesting the existence of predicted redundant TREX components. UIF (Hautbergue et al. 2009), Chtop (Chang et al. 2013), Luzp4 (Viphakone et al. 2015), PDIP3, and ZC11A (Folco et al. 2012) have been identified as such functionally redundant factors, adding further to the complexity of mammalian mRNP compositions. The yeast Tho1 homolog, CIP29/SARNP, also associates with TREX through UAP56 and is implicated in mRNP packaging (Dufu et al. 2010).

Poly(A) binding proteins (PABPs).

Near the end of transcription, the 3′ end of the mRNA is cleaved and a poly(A) tail is synthesized (Boreikaitė and Passmore 2023; Rodríguez‐Molina and Turtola 2023). These processes are mediated by a multi‐complex cleavage and polyadenylation machinery, composed of subcomplexes, CPF, CFIA, and CFIB in yeast, and CPSF, CstF, CFIm, and CFIIm in humans. Nuclear poly(A) binding proteins are involved in these processes and contribute to controlling the length of the poly(A) tail (Rodríguez‐Molina and Turtola 2023; Stewart 2019; Wigington et al. 2014). These processes are highly linked to mRNP packaging and export with some components incorporated into mRNPs. For example, the yeast CFIB protein, Hrp1, shuttles between the nucleus and cytoplasm and is involved in a cytoplasmic mRNA decay pathway, NMD, indicating that Hrp1 associates with mRNP during 3′ processing and is exported to the cytoplasm as a component of mRNPs (González et al. 2000; Kessler et al. 1997). Recently, it has been shown that Hrp1 directly interacts with the mRNA export receptor, Mex67, and is involved in the quality control to ensure the export of properly 3′ processed mRNAs (Li et al. 2023).

The yeast genome encodes two essential poly(A) binding proteins, Nab2 and Pab1. The majority of Nab2 localizes in the nucleus with a central role in nuclear poly(A) tail length control (Turtola et al. 2021). Nab2 interacts with Yra1 and the mRNA export receptor Mex67; thus, it is considered a major constituent of nuclear mRNPs supporting mRNA export (Asada et al. 2023; Green et al. 2002; Iglesias et al. 2010). Pab1, while mainly cytoplasmic with functions in translation (S. H. Kessler and Sachs 1998), shuttles between the nucleus and cytoplasm with roles in poly(A) tail length control and mRNA export (Brune et al. 2005; Turtola et al. 2021). Because the pab1 nuclear import mutant only shows a defect in poly(A) tail length when the available Nab2 pool is limited, Pab1 likely has a minor role or regulates only a subset of genes in the nucleus (Turtola et al. 2021). In humans, the nuclear poly(A) binding protein PABPN1 plays a major role in poly(A) tail length control and is engaged with mRNPs in the nucleoplasm (Bear et al. 2003). The Nab2 ortholog ZC3H14 is also involved in poly(A) tail length control (Kelly et al. 2014). ZC3H14 physically interacts with the THO complex and is required for proper processing and quality control (Morris and Corbett 2018), suggesting a role in mRNP packaging, similarly to Nab2.

BOX 2. Co‐Opting Host mRNA Export Machinery for Preferential Export of Viral RNA.

In human cells, alterations in the composition of nuclear mRNPs are known to occur in the context of disease, including viruses co‐opting RBPs for the processing and export of their own viral transcripts while also disrupting host mRNP formation and gene expression (Guha and Bhaumik 2021). For example, the ICP27 family protein in herpes simplex virus‐1 (HSV‐1) directly interacts with ALYREF to recruit NXF1‐NXT1 (Figure 3D), facilitating viral mRNA export (Chen et al. 2002; Koffa et al. 2001; Soto‐Machuca et al. 2025). Notably, while ALYREF usually localizes within nuclear speckles, during HSV‐1 infection it re‐localizes to a viral replication compartment (Chen et al. 2005), suggesting depletion of the available ALYREF pool for host cell mRNA export. Similarly, ICP27 homologs in other herpesviruses interact with TREX components, as well as the other NXF1‐NXT1 adaptor RBPs, including ALYREF (Boyne et al. 2008; Malik et al. 2004; Williams et al. 2005), UAP56 (Lischka et al. 2006), UIF (Jackson et al. 2011), CIP29/SARNP and Chtop (Schumann et al. 2016), and SR proteins (Ote et al. 2009). In the case of influenza A virus (IAV) infection, the non‐structural protein 1 (NS1), a major virulence protein encoded in the IAV genome, directly interacts with NXF1‐NXT1, and structural analysis revealed that this interaction inhibits the NXF1‐NXT1 association with FG‐nucleoporins, which is required for host mRNP, leading to an mRNA export block (Zhang et al. 2019). Although the detailed mechanism is not fully understood, the IAV mRNA can escape from this inhibition and is efficiently exported to the cytoplasm via the NS1‐binding protein (Zhang et al. 2024). Similar to NS1 in IAV, non‐structural protein 1 (Nsp1) in the severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) interacts with NXF1 and inhibits the interaction of NXF1 with the adaptor protein ALYREF and nucleoporins, leading to the inhibition of host cell nuclear mRNA export (Zhang et al. 2021). The Nsp14 protein encoded in the SARS‐CoV‐2 also inhibits host cell mRNA export (Katahira et al. 2023). Nsp14 is a bifunctional viral replicase subunit, which is composed of the exoribonuclease and N7‐methyltransferase (N7‐MTase) domains. The N7‐MTase methylates GTP and produces m⁷GTP, which acts as a cap mimic, depleting functional CBC (Katahira et al. 2023). Together, these examples highlight how viral pathogenesis is supported through virus‐specific mRNP compositions established via interactions between viral proteins and host cell nuclear mRNP components.

4.1. mRNP Assembly and Maturation Dynamics

At the transcription site, nascent mRNA processing and packaging is directed by RBPs, many of which are known to bind the C‐terminal domain (CTD) of RNAPII co‐transcriptionally in a phosphorylation‐dependent manner (Harlen and Churchman 2017; Hsin and Manley 2012; Singh et al. 2022; Venkat Ramani et al. 2021), including TREX complex components (MacKellar and Greenleaf 2011; Meinel et al. 2013). Temporal models of co‐transcriptional processing and mRNP assembly are based largely on known functions of RBPs, binding site locations within transcripts, and Chromatin immunoprecipitation (ChIP) density at active genes. For example, it may be assumed that RBPs with a 3′ bias in the mRNA would be recruited later than those showing 5′ proximal peaks in binding, but in most cases direct evidence of recruitment timing is lacking. As such, many questions remain as to how mRNP assembly is coordinated in vivo, including the requirement for varied processing based on gene features (e.g., promoter, transcript length, etc.), as illustrated in Figure 3. This is in large part due to the technical challenges of tracking mRNP assembly in vivo at a single transcription site.

To address this, we recently employed a live‐cell imaging assay that can monitor temporal dynamics of co‐transcriptional RBP recruitment to an inducible gene array in S. cerevisiae (Wechsler et al. 2025). This was motivated by previous work employing tandem gene arrays in mammalian cells to visualize enrichment of RBPs at transcription sites (Brody et al. 2011; Hochberg‐Laufer et al. 2019; Janicki et al. 2004). Using inducible gene arrays, with two different promoters and the same coding sequence (GFA1), recruitment of endogenously tagged proteins was observed at active transcription sites and arrival times quantified for a wide variety of proteins with roles in transcription, mRNP processing, and mRNP packaging, including TREX complex components (Wechsler et al. 2025). Notably, this demonstrated Yra1 was among the earliest factors recruited to the transcription site, with recruitment occurring prior to and independent of the THO complex. Furthermore, recruitment was delayed in cbp80Δ as well as when the RRM domain of Yra1 is deleted (Yra1ΔRRM). The RRM domain in Yra1 was implicated previously as a hot spot for protein–protein interactions (Bonneau et al. 2023), and human structural data shows a direct interaction between the ALYREF RRM domain and the cap binding complex (Clarke et al. 2024). This suggests a model where the early arrival of Yra1 is facilitated by protein interactions, including between Yra1 and CBC, as well as the RNAPII CTD (MacKellar and Greenleaf 2011), poising Yra1 to immediately engage the emerging nascent RNA to aid productive elongation and mRNP packaging via RNA annealing.

It is not known if the temporal dynamics of ALYREF are the same or different in metazoan systems, given the central role of splicing and the EJC in mRNP assembly and compaction (Pacheco‐Fiallos et al. 2023). However, the arrival timing of Yra1 aligns well with structural data in humans, placing ALYREF at the mRNP core (Pacheco‐Fiallos et al. 2023), the role of THO in promoting higher Yra1 stoichiometries as determined by mRNP‐SiMPull (Asada et al. 2023), and the emerging model of mRNP assembly centered on a protein–protein interaction network of IDR‐containing proteins (Bonneau et al. 2023). It is also notable that the early arrival of Yra1 and the initiation of timely mRNA packaging via THO/TREX may be linked to the prevention of R‐loops (Infantino and Stutz 2020; Luna et al. 2019). Indeed, mutations in many different mRNP biogenesis and processing components increase R‐loop formation, and it is suggested that mRNP packaging prevents R‐loop formation by preventing the RNA from hybridizing with single‐strand DNA (Luna et al. 2024). Interestingly, it was recently demonstrated that ALYREF can directly bind DNA–RNA hybrids and R‐loops in vitro, and together with UAP56 resolve R‐loops (Bhandari et al. 2024), raising the possibility of RBP‐directed events during mRNP packaging that actively resolve R‐loops. We expect this to be an active area of future research given the links between R‐loops, gene expression, genome instability, and human disease (Aguilera and Aguilera 2025; Beghѐ et al. 2025; Mudiyanselage et al. 2025; Stötzel et al. 2025).

Once transcription terminates and transcripts are cleaved and polyadenylated, the dynamics of subsequent maturation events within the nucleus leading to export are generally unclear. It is expected this entails the association and dissociation of varied RBPs from the mRNPs, but these events are difficult to capture (Figure 1). In yeast, nuclear residencies are typically quite short, with transcripts thought to be exported rapidly after release. In mammalian cells, significant processing is reported to occur following transcript release from the transcription site, including within nuclear speckles (Figure 1), though many open questions remain regarding the frequency, dynamics, and mechanisms governing these post‐transcriptional processing events (Carrocci and Neugebauer 2024; Choquet et al. 2025; Shenasa and Bentley 2023; Faber et al. 2022; Galganski et al. 2017; Hasenson and Shav‐Tal 2020). Similarly, SR‐proteins located at nuclear speckle have been shown to mediate gene‐specific regulation by retaining mRNAs with GA‐rich RNA sequences, thus buffering the expression of a class of genes with disordered low‐complexity domains (LCDs) that can be toxic when expressed at high levels in human cells (Faraway et al. 2023). Most recently, it was demonstrated that under conditions of transcriptional inhibition in human cells, mRNAs accumulate in nuclear speckles bound by ALYREF and NXF1, where they are held until mRNA export is reinitiated once the inhibition is lifted (Williams et al. 2025). The TREX complex is known to be enriched in nuclear speckles (Akef et al. 2013; Dias et al. 2010; Masuda et al. 2005; Wang et al. 2018) and data suggest roles in regulating the storage and release of transcripts from speckles (Akef et al. 2013; Dias et al. 2010; Teng and Wilson 2013; Wang et al. 2018). These observations suggest that THO/TREX and other RBPs may engage mRNAs in nuclear speckles to maintain mRNA compaction, protecting these complexes from degradation by the RNA exosome and other RNA decay machinery. More broadly, it suggests that nuclear residence time is going to be highly variable across transcripts and regulated in response to cellular conditions.

Toward further understanding nuclear mRNA processing dynamics, two recently developed methods employ metabolic labeling to characterize the dynamics of the mRNA lifecycle transcriptome‐wide in mammalian cells (Choi et al. 2024; Ietswaart et al. 2024). With TimeLapse‐seq (Ietswaart et al. 2024), cells are pulsed labeled over a time course, and RNA is biochemically purified and sequenced from chromatin, nucleus, cytoplasm, and polysomes, which in combination with mathematical modeling, enabled evaluation of transcript half‐lives in each compartment as well as estimated rates of nuclear export, polysome loading, and turnover. This demonstrated vast kinetic heterogeneity among transcripts and identified groups of genes with notable trends, like high rates of nuclear degradation. Choi et al. (2024) employ a pulse‐chase time course to label RNA, crosslink to preserve RNA–protein interactions, pull down polyadenylated RNAs, and then use mass spectrometry to determine RBPs associated with labeled RNAs at each time point. From this, they identified seven clusters of RBPs with binding patterns ranging from early (I) to late (VII), with many trends aligning with known RBP functions. Of note, they identify ALYREF and UAP56, as well as core EJC proteins, as relatively late binders (cluster V) that join after the major export factor NXF1 (Choi et al. 2024). Currently, with the bulk nature of the experiment and use of oligo‐dT to perform the isolations, it remains to be seen if these patterns of RBP binding represent an alternate pathway of mRNP assembly or reflect a technical bias for a particular population of mRNAs due to the purification scheme and/or transcript features. Overall, these observations of mRNP dynamics involving nuclear speckles (Williams et al. 2025), kinetic heterogeneity across transcript processing (Ietswaart et al. 2024), and alternate patterns of RBP binding (Choi et al. 2024; Tuck and Tollervey 2013) underscore the need for more work to understand how variation in mRNP assembly and maturation come together to regulate gene expression.

4.2. Docking and Remodeling for Nuclear Export

Ultimately, nuclear mRNPs must be exported through NPCs to continue along the gene expression pathway. Export competency emerges from upstream processing events that link mRNA maturation (e.g., m7G cap, poly(A) tail, exon junctions) with key RBPs that serve as adaptors for the major export receptor heterodimer (NXF1‐NXT1 in humans, Mex67‐Mtr2 in yeast). The presence of the export receptor ultimately provides access to the NPC, with export efficiency further being regulated by other RBP‐directed binding events with the nuclear basket and nucleoporins (Bensidoun et al. 2021). Interestingly, in yeast, nuclear basket formation was found to be influenced by RNA metabolism, and a subset of RNAs was found to be associated with basket‐less NPCs, suggesting an alternative route of export through pores lacking a basket (Bensidoun et al. 2022). The RNAs in this population were enriched for shorter transcripts with shorter poly(A) tails, suggesting possible selectivity in export, but the mechanisms conferring export in basket‐less NPCs require investigation.

Single particle tracking studies have followed mRNP export kinetics in both yeast and mammalian cells, finding that in both cases mRNPs often scan the nuclear periphery and dock at the nuclear basket of the NPC prior to export (Grünwald and Singer 2010; Mor et al. 2010; Saroufim et al. 2015; Smith et al. 2015). The purpose and mechanism of this scanning and docking at the pore are not entirely understood, but may be a mechanism conferring selectivity (Bensidoun et al. 2021). In yeast, the poly(A) binding protein, Nab2, physically interacts with the nuclear basket component, Mlp1/2 (Fasken et al. 2008; Green et al. 2003). Disruption of the Nab2‐Mlp1/2 interaction impairs mRNP scanning and docking, causing frequent release of mRNPs back into the nucleoplasm (Saroufim et al. 2015). This indicates that interactions between mRNP components and the nuclear basket support productive docking of the mRNPs onto the pore for export. Depletion of the orthologous human nuclear basket protein TPR disrupts mRNA export, particularly for short genes with few introns, suggesting a conserved role of the nuclear basket in facilitating mRNP interactions with the pore (Aksenova et al. 2020; Lee et al. 2020).

Along the mRNA export path, nuclear mRNPs must be remodeled for use in the cytoplasm and to infer directionality to the export process. This remodeling in part occurs at the cytoplasmic side of the NPC (Köhler and Hurt 2007); however, recent studies also suggest that mRNP remodeling takes place within the nucleus and at the nuclear basket of the NPC. Specifically, the THO complex coats the surface of human mRNPs, with recent biochemical and structural analyses proposing a model where the THO complex is dissociated through the competitive binding of SARNP to an overlapping binding site on UAP56 (Hohmann et al. 2024). This establishes conditions for a second proposed remodeling at the nuclear basket mediated by the TREX‐2 complex. TREX‐2 is an evolutionarily conserved complex that localizes to NPCs by association with the nuclear basket (Fischer et al. 2002; Umlauf et al. 2013). In yeast, TREX‐2 is composed of Sac3, Thp1, Sus1, Cdc31, and Sem1, while in humans the subunits are GANP, PCID2, ENY2, DSS1, and CETN2 or CETN3. Mutation of TREX‐2 causes nuclear mRNA accumulation, indicating that TREX‐2 mediates mRNP export (Ellisdon et al. 2012). Most recently, structural studies identified an interaction between TREX‐2 and UAP56/Sub2 as key to the remodeling of mRNPs for export at the pore, in both human and yeast (Hohmann et al. 2024; Xie et al. 2025). These studies structurally characterized the TREX‐2 and UAP56/Sub2 interaction by cryo‐EM, and in both cases identified a conserved loop in a TREX‐2 subunit (GANP/Sac3) that stimulates the ATPase activity of UAP56/Sub2 and promotes the release of UAP56/Sub2 from RNA (Hohmann et al. 2024; Xie et al. 2025). Additionally, a complex was recently identified in human cells consisting of TREX‐2 subunits PCID2 and DSS1 with an alternative scaffold subunit, LENG8, that is a paralog of GANP (Clarke et al. 2025). This complex, termed TREX‐2.1, was also found to bind to UAP56, stimulating its ATPase activity and RNA release through the same conserved trigger loop as GANP (Clarke et al. 2025). In contrast to TREX‐2, which is localized predominantly to NPCs, TREX‐2.1 is localized throughout the nucleoplasm, suggesting it may act to regulate UAP56 activity in an alternative context such as splicing or decay (Clarke et al. 2025). While LENG8 has an ortholog (THP3) in S. cerevisiae, it remains to be seen whether the formation of a TREX‐2.1‐like alternative complex and stimulation of Sub2 activity are conserved.

Overall, the binding and stimulation of Sub2/UAP56 by TREX‐2 suggests a model wherein TREX‐2 triggers mRNP export via removal of the DEAD‐box ATPase UAP56/Sub2 at the nuclear basket (Figure 1) (Hohmann et al. 2024; Xie et al. 2025). This indicates perinuclear scanning may be a byproduct of unproductive UAP56/Sub2–TREX‐2 binding at the NPC, due to lack of UAP56/Sub2 incorporation in mRNPs and/or lack of available TREX‐2 at those pores, perhaps making this interaction a means of selectivity for properly matured mRNPs. These data support a conserved mechanism for unloading of UAP56/Sub2 from mRNPs at the nuclear face of the NPC for export and, critically, bridge the roles of TREX in mRNP packaging to export competency and remodeling at the NPC to regulate nuclear export.

4.3. Loading the mRNA Export Receptor for Export Through an NPC

The mRNA export receptor, Mex67‐Mtr2/NXF1‐NXT1, mediates interaction of mRNPs with the central channel of the NPC, facilitating export into the cytoplasm. One long‐standing model is that the export receptor is loaded onto the mRNA co‐transcriptionally via interaction with adaptor proteins. This is supported by the data showing Mex67 and NXF1 can be detected by ChIP (Chen et al. 2019; Gwizdek et al. 2006), and in the case of NXF1, CLIP‐seq analysis showed detection of exon‐intron sequence reads, indicating that NXF1 can bind to pre‐mRNA during processing (Müller‐McNicoll et al. 2016). However, recent advances in imaging techniques have suggested a model where Mex67‐Mtr2 independently functions at the NPC, mediating export at the pore upon encountering mRNPs. In yeast, fluorescent correlation spectroscopy (FCS) analysis to assess the diffusion coefficient of the fluorescently tagged protein revealed that Mex67 diffusion behavior is more closely related to a free protein in contrast to a large molecular assembly like an mRNP (Derrer et al. 2019). Moreover, the lethality of a MEX67 gene deletion can be rescued by expressing a fusion of Mex67 and the nucleoporin Nup116, suggesting that the essential function of Mex67 occurs at the NPC, rather than loading being necessary prior to docking of the mRNP to the pore (Derrer et al. 2019). Consistent with these observations, live imaging to track single mRNAs in the mex67‐5 mutant showed a greater impact on mRNP cytoplasmic release than docking and translocation (Smith et al. 2015). Furthermore, single‐molecule analyses of mRNPs showed that Mex67 is rarely associated with mRNPs bound by the export adaptor proteins Yra1, Nab2, and Npl3 (Asada et al. 2023). In addition, RNA‐independent localization of NXF1 to NPCs is observed in mammalian cells, and like in yeast, the diffusion rate of NXF1 within the nucleoplasm showed that NXF1 behaves as a free protein rather than a large complex (Ben‐Yishay et al. 2019). These data strongly indicate mRNP‐binding and the promotion of mRNA export under steady‐state growth conditions are most commonly occurring at NPCs (Figure 1). Nonetheless, it remains possible that Mex67‐Mtr2/NXF1‐NXT1 functions to support mRNP export via distinct modes that may be gene‐specific. For example, as noted previously, stress‐responsive mRNAs associate with Mex67‐Mtr2 without the need for adaptor proteins, allowing for rapid export of these mRNAs (Figure 2B) (Zander et al. 2016). In the case of stress, where and when Mex67 joins the mRNP in relation to mRNP assembly at transcription sites vs. binding to NPCs is not known.

5.1. Characterizing Nuclear mRNP Heterogeneity

As supported by recent works, including those discussed above, transcriptome‐wide nuclear mRNPs vary not only in their mRNA sequences but also in protein composition, size, and organization. While published research has begun to characterize this heterogeneity, there is still much to know about the mechanisms responsible for generating differential nuclear mRNP features and how they contribute to differential gene expression outcomes. It is expected that gene and transcript features (e.g., promoter, sequence, length, presence of introns, RNA modifications, polyA‐tail length) play a central role, but a comprehensive characterization is lacking and will be important to address in future work. This motivates the need for improved techniques to interrogate mRNP composition and structure in a gene‐specific manner at single molecule resolution.

In addition to transcriptome‐wide heterogeneity, there is diversity across the mRNPs produced from the same gene, including compositional changes over time as mRNPs progress through gene expression, changes dictated by external environmental conditions (e.g., stress), and diversity arising from stochastic events during gene expression (e.g., splicing order, transcription‐replication conflict, presence of an R‐loop, error in processing, etc.). This heterogeneity is exemplified by changes in S. cerevisiae nuclear mRNP compositions at moderately elevated temperature (37°C) observed with mRNP‐SiMPull despite a constant transcriptome (Asada et al. 2023). We expect that to fully understand gene expression regulation, an understanding of the population of mRNPs coming from individual genes is needed.

These open questions necessitate improved technologies to interrogate the composition and architecture of individual mRNPs with gene specificity. Our group is currently working to implement a gene‐specific mRNP‐SiMPull, extending the capabilities of our previous work to characterize mRNP composition for transcripts of individual genes. Furthermore, the extension of approaches to structurally characterize mRNPs, such as cryo‐EM, to characterize mRNPs at a gene‐specific level is critical to better understand the relationship between transcript features and structure. Observed heterogeneity in particle size and shape at present cannot be correlated to any gene features, so it is not known how different aspects of the transcript contribute to overall packaging and conformation(s).

5.2. Organizing Principles of RNA Within Nuclear mRNPs

Many open questions need to be addressed with respect to the organization of mRNA in mRNPs and the role RNA structure plays in mRNP packaging. These include whether mRNAs have a repeating structure/organization that is reliant on length and/or sequence features, whether compaction is driven largely by intramolecular interactions or RBPs, and whether mRNA structure is actively directing gene expression outcomes. The most recent efforts in probing yeast and mammalian nuclear mRNAs have found high levels of structural similarities to cytoplasmic transcripts (Schärfen et al. 2025; Sun et al. 2019). This suggests compaction may be accomplished through long‐range contacts or tertiary structures not captured with these structure probing experiments, or that additional local base pairing interactions beyond those observed may be highly dynamic or heterogeneous across particles, making them difficult to capture, even with current depths of sequencing. As such, further data characterizing overall nuclear mRNA conformations will help to inform how this compacted packaging is achieved. Finally, with emerging data suggesting previously unappreciated breadth of mRNA base modifications and the advent of new technologies to map modified sites transcriptome‐wide (Boo and Kim 2020; Gilbert and Nachtergaele 2023; Sun et al. 2023), it will be necessary to explore how these modifications influence nuclear mRNP composition, organization, and dynamics, as they are expected to influence all of these aspects to varying degrees.

Overall, we expect that continued advances in gene‐specific interrogation methods for mRNPs will reveal mechanisms that generate their heterogeneity and better understanding of how these diverse particles shape gene expression regulation. Such insights will ultimately provide fundamental principles of RNA packaging and regulation, deepening our understanding of how mRNP diversity contributes to gene expression outcomes.

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Data Availability Statement

Data sharing are not applicable to this article as no new data were created or analyzed in this study.