Rev and the fate of pre-mRNA in the nucleus: implications for the regulation of RNA processing in eukaryotes.
Although a great deal is known about the regulation of gene expression in terms of transcription, relatively little is known about the modulation of pre-mRNA processing. In this study, we exploited a genetically regulated system, human immunodeficiency virus type 1 (HIV-1) and its trans-activator Rev, to examine events that occur between the synthesis of pre-mRNA in the nucleus and the translation of mRNA in the cytoplasm. Unlike the majority of eukaryotic pre-mRNAs whose introns are efficiently recognized and spliced prior to nucleocytoplasmic transport, HIV-1 mRNAs containing functional introns must be exported to the cytoplasm for the expression of many viral proteins. Using human T cells containing stably integrated proviruses, we demonstrate that such incompletely spliced viral mRNAs are exported to the cytoplasm only in the presence of the Rev trans-activator. In the absence of Rev, these intron-containing RNAs are sequestered in the T-cell nucleus and either spliced or, more commonly, degraded. Because Rev does not inhibit the expression of fully spliced viral mRNA species in T cells, we propose that Rev, rather than inhibiting viral pre-mRNA splicing, is acting here both to prevent the nuclear degradation of HIV-1 pre-mRNAs and to induce their translocation to the cytoplasm. Taken together, these findings indicate that the cellular factors responsible for the nuclear retention of unspliced pre-mRNAs, although most probably splicing factors, do not invariably commit these RNAs to productive splicing and can, instead, program such transcripts for degradation.
Malim
M H
MH
Howard Hughes Medical Institute, University of Pennsylvania School of Medicine, Philadelphia 19104-6148.
Cullen
B R
BR
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000382:microbiology; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D015694:Gene Products, rev / Q000378:metabolism*; D015757:Genes, rev; D015497:HIV-1 / Q000235:genetics* / Q000502:physiology; D000882:Haplorhini; D006801:Humans; D007438:Introns; D016133:Polymerase Chain Reaction; D011233:Precipitin Tests; D014176:Protein Biosynthesis; D012322:RNA Precursors / Q000378:metabolism*; D012323:RNA Processing, Post-Transcriptional; D014161:Transduction, Genetic; D014764:Viral Proteins / Q000096:biosynthesis; D014779:Virus Replication; D054321:rev Gene Products, Human Immunodeficiency Virus
D015694:Gene Products, rev; D012322:RNA Precursors; D014764:Viral Proteins; D054321:rev Gene Products, Human Immunodeficiency Virus