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NMD3 Regulates Both Mrna and Rrna Nuclear Export In Nucleic Acids Research Advance Access published April 14, 2015 Nucleic Acids Research, 2015 1 doi: 10.1093/nar/gkv330 NMD3 regulates both mRNA and rRNA nuclear export in African trypanosomes via an XPOI-linked pathway Melanie Buhlmann¨ 1,†, Pegine Walrad1,2,†,EvaRico1, Alasdair Ivens1, Paul Capewell1, Arunasalam Naguleswaran3, Isabel Roditi3 and Keith R. Matthews1,* 1Centre for Immunity, Infection and Evolution, Institute for Immunology and Infection Research, School of Biological Sciences, Kings Buildings, University of Edinburgh, West Mains Road, Edinburgh EH9 3JT, UK, 2Centre for Immunology and Infection, Department of Biology, University of York, YO10 5DD, UK and 3Institute of Cell Biology, University of Bern, CH-3012 Bern, Switzerland Received March 02, 2015; Revised March 30, 2015; Accepted March 31, 2015 Downloaded from ABSTRACT INTRODUCTION Trypanosomes mostly regulate gene expression The compartmentalization of nuclear DNA away from the through post-transcriptional mechanisms, particu- translational apparatus in the cytoplasm of eukaryotic cells larly mRNA stability. However, much mRNA degra- requires elaborate mechanisms to achieve the regulated ex- http://nar.oxfordjournals.org/ dation is cytoplasmic such that mRNA nuclear ex- port of RNA to enable gene expression (1,2). The multiple port must represent an important level of regulation. stages of nuclear export provide several potential regulatory steps to ensure that RNAs of different function can be held Ribosomal RNAs must also be exported from the inactive until fully matured, localized or targeted for cyto- nucleus and the trypanosome orthologue of NMD3 plasmic degradation (3,4). This prevents incorrectly or in- has been confirmed to be involved in rRNA process- completely processed RNAs from perturbing normal cel- ing and export, matching its function in other or- lular functions by interfering with important cellular pro- ganisms. Surprisingly, we found that TbNMD3 deple- cesses, or generating products that would be deleterious to tion also generates mRNA accumulation of procyclin- the cell (5,6). Such RNAs can include nascent ribosomal at World Trade Institute on May 8, 2015 associated genes (PAGs), these being co-transcribed RNA subunits, tRNAs, incorrectly processed mRNAs, nu- by RNA polymerase I with the procyclin surface clear RNAi targets that require trafficking to the cytoplasm antigen genes expressed on trypanosome insect for degradation, as well as bulk mRNAs. Hence, in addi- forms. By whole transcriptome RNA-seq analysis tion to transcription, mRNA stability and translation, the of TbNMD3-depleted cells we confirm the regula- export pathway for a variety of cellular RNAs provides con- siderable scope for the cell to control the expression and tion of the PAG transcripts by TbNMD3 and using function of transcripts (4). Such regulatory pathways have reporter constructs reveal that PAG1 regulation is been extensively studied in both yeast and mammalian sys- | downloaded: 7.10.2021 mediated by its 5 UTR. Dissection of the mecha- tems and include complex rRNA maturation and export nism of regulation demonstrates that it is not de- steps (7) and the nonsense-mediated decay (NMD) of in- pendent upon translational inhibition mediated by correctly processed mRNAs (8). TbNMD3 depletion nor enhanced transcription. How- African trypanosomes provide an interesting opportu- ever, depletion of the nuclear export factors XPO1 nity to dissect the pathways of gene regulation in evolu- or MEX67 recapitulates the effects of TbNMD3 deple- tionarily divergent organisms (9,10). These organisms, im- tion on PAG mRNAs and mRNAs accumulated in the portant pathogens of humans and livestock in sub-Saharan nucleus of TbNMD3-depleted cells. These results in- Africa, diverged very early in the eukaryotic lineage and ex- voke a novel RNA regulatory mechanism involving hibit several novelties of gene expression that have attracted considerable attention. This includes their co-transcription the NMD3-dependent nuclear export of mRNA car- of functionally unrelated genes as part of polycistronic tran- gos, suggesting a shared platform for mRNA and scription units (11) and their extreme reliance on post- rRNA export. transcriptional mechanisms of gene expression control ne- cessitated by this genome organization (12). Particularly, mRNAs are generated from polycistronic transcription *To whom correspondence should be addressed. Tel: +44 131 6513639; Fax: +44 131 6513670; Email: [email protected] https://doi.org/10.7892/boris.68789 †These authors contributed equally to the paper as first authors. Disclaimer: The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. C The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research. // / / / / source: This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http: creativecommons.org licenses by 4.0 ), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. 2 Nucleic Acids Research, 2015 units by the coupled processes of 5 trans-splicing of a 39- role of both highly conserved, and parasite-specific, com- nt capped leader sequence and 3 polyadenylation (13,14). ponents in this fundamentally important export pathway These RNA processing steps allow trypanosomes to ex- (33–37). ploit the transcription of protein coding genes by RNA In this study, we have made the surprising discovery polymerase I in order to generate the high levels of sur- that post-transcriptional gene silencing by RNAi of try- face protein transcripts necessary for their survival or fit- panosome NMD3 results in a striking increase in PAG mR- ness in the mammalian bloodstream or tsetse fly midgut NAs in procyclic form trypanosomes, which is not mediated (15,16). In the tsetse midgut, the surface coat is composed of by the effects of NMD3 depletion on transcription, or trans- different isoforms of procyclin. These isoforms (EP procy- lation. Rather, our results invoke a novel regulatory step clin, GPEET procyclin) show differential expression during dependent upon nuclear export of the mRNA, PAG tran- the parasite’s maturation in the tsetse fly (17) and are tran- scripts representing an mRNA cargo with particular cyto- scribed from several transcription units on different chro- plasmic instability whose trafficking is dependent on a nu- mosomes in the parasite genome (18). These are transcribed clear export pathway conventionally involved in the matu- by RNA polymerase 1 (pol I) and contain unrelated genes of ration and export of large subunit ribosomal RNAs (38). unknown function, namely the procyclin-associated genes (PAGs)(19,20). Procyclin/PAG genes are believed to be tran- MATERIALS AND METHODS scribed in the nucleolus since procyclic form parasites do Downloaded from not possess a detectable expression site body, an extranucle- Trypanosomes culture olar site of pol I transcription for the surface antigen genes of the bloodstream form (21). Although PAG transcripts For developmental expression analysis using pleomorphic are generated from the same transcription unit as the pro- trypanosomes, pleomorphic slender cells were harvested cyclin genes, their overall mRNA abundance is much lower from a mouse 3 days post-infection, intermediate cells were (19,22–24). harvested 4 days post-infection and stumpy cells were har- http://nar.oxfordjournals.org/ The understanding of regulated gene expression in try- vested 6 days post-infection. Bloodstream and procyclic panosomes through the action of protein factors remains parasites were grown in culture as described (39). For stable × 8 × 7 very incomplete. Nonetheless, the trypanosome genome en- transfection 1 10 procyclic form or 4 10 bloodstream codes an abundance of RNA binding proteins, many of form cells were subjected to nucleofection with the Nucleo- which are unique to these evolutionarily divergent organ- fector system (Amaxa) using programs X-014 (PCF) or X- isms (12,25,26). The characterization of these kinetoplastid- 001 (BSF) as described in (40) and selected using the appro- ␮ / ␮ / specific factors has revealed a common role in mRNA sta- priate drugs: puromycin, 1–2 g ml (PCF) or 0.5 g ml (BSF), hygromycin: 20 ␮g/ml (PCF) or 2.5 ␮g/ml (BSF), bility and translation, often involved in regulating the de- at World Trade Institute on May 8, 2015 ␮ / ␮ / velopment through the many stages that accompany pro- phleomycin: 5–10 g ml (PCF) or 1 g ml (BSF). gression of the parasites through their complex life cycle RNAi lines of TbNMD3 and XPO1 were created using (27). In addition to these specific factors, trypanosomatids the stem loop vector pALC14 (41). Inserts were amplified by also encode a core set of conserved protein factors with polymerase chain reaction (PCR) using primers detailed in predicted functions in gene expression. These include many Supplementary Table S1. For transfection pALC14 vectors well characterized components of the translational machin- were linearized with NotI prior to transfection. ery, as well as proteins associated with RNA processing, degradation and nuclear export (28,29). In particular, bioin- Report constructs formatics analyses of the genomes of kinetoplastid parasites and other eukaryotic groups including a broad group of The constitutive CAT reporter construct was based on the expression vector pHD449 (42), as described in (43). The opisthokonta have revealed a
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