NMD3 regulates both mRNA and rRNA nuclear export in African trypanosomes via an XPOI-linked pathway

Bühlmann, M., Walrad, P., Rico, E., Ivens, A., Capewell, P. , Naguleswaran, A., Roditi, I. and Matthews, K. R. (2015) NMD3 regulates both mRNA and rRNA nuclear export in African trypanosomes via an XPOI-linked pathway. Nucleic Acids Research, 43(9), pp. 4491-4504. (doi: 10.1093/nar/gkv330) (PMID:25873624) (PMCID:PMC4482084)

Abstract

Trypanosomes mostly regulate gene expression through post-transcriptional mechanisms, particularly mRNA stability. However, much mRNA degradation is cytoplasmic such that mRNA nuclear export must represent an important level of regulation. Ribosomal RNAs must also be exported from the nucleus and the trypanosome orthologue of NMD3 has been confirmed to be involved in rRNA processing and export, matching its function in other organisms. Surprisingly, we found that TbNMD3 depletion also generates mRNA accumulation of procyclin-associated genes (PAGs), these being co-transcribed by RNA polymerase I with the procyclin surface antigen genes expressed on trypanosome insect forms. By whole transcriptome RNA-seq analysis of TbNMD3-depleted cells we confirm the regulation of the PAG transcripts by TbNMD3 and using reporter constructs reveal that PAG1 regulation is mediated by its 5′UTR. Dissection of the mechanism of regulation demonstrates that it is not dependent upon translational inhibition mediated by TbNMD3 depletion nor enhanced transcription. However, depletion of the nuclear export factors XPO1 or MEX67 recapitulates the effects of TbNMD3 depletion on PAG mRNAs and mRNAs accumulated in the nucleus of TbNMD3-depleted cells. These results invoke a novel RNA regulatory mechanism involving the NMD3-dependent nuclear export of mRNA cargos, suggesting a shared platform for mRNA and rRNA export.

• Item Type: Articles
• Additional Information: Funding: The Wellcome Trust [WT088293, WT095831 to K.M.]; the BBSRC [BB/D526237/1 to M.B. and K.M.]; the UK Medical Research Council [MR/L00092X/1 to P.W.]; the Swiss National Science Foundation [31003A-144142 to I.R.]; Howard Hughes Medical Institute [55007650 to I.R.]. Funding for open access charge: the Wellcome Trust.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Capewell, Dr Paul
• Authors: Bühlmann, M., Walrad, P., Rico, E., Ivens, A., Capewell, P., Naguleswaran, A., Roditi, I., and Matthews, K. R.
• College/School: College of Medical Veterinary and Life Sciences > School of Biodiversity, One Health & Veterinary Medicine
• Journal Name: Nucleic Acids Research
• Publisher: Oxford University Press
• ISSN: 0305-1048
• ISSN (Online): 1362-4962
• Published Online: 14 April 2015
• Copyright Holders: Copyright © 2015 The Authors
• First Published: First published in Nucleic Acids Research 43(9): 4491-4504
• Publisher Policy: Reproduced under a Creative Commons License