Specific binding of polypyrimidine tract binding protein and hnRNP A1 to HIV-1 CRS elements

Black, Alexander C.; Luo, Jie; Chun, Susan; Bakker, Andreas; Fraser, John K.; Rosenblatt, Joseph D.

doi:10.1007/bf00284648

Cited by 35 publications

(30 citation statements)

References 43 publications

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“…We consider it likely that these and/or additional factors may facilitate INS recognition in vivo or play a role at later steps. In fact, hnRNP A1 has been shown to participate in INS function, possibly by direct interactions (9,41). The possible mechanistic roles of such factors in INS-mRNA regulation remain to be addressed.…”

Section: Discussionmentioning

confidence: 99%

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PSF Acts through the Human Immunodeficiency Virus Type 1 mRNA Instability Elements To Regulate Virus Expression

Zolotukhin

Michałowski

Bear

et al. 2003

Molecular and Cellular Biology

122

145

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Human immunodeficiency virus type 1 (HIV) gag/pol and env mRNAs contain cis-acting regulatory elements (INS) that impair stability, nucleocytoplasmic transport, and translation by unknown mechanisms. This downregulation can be counteracted by the viral Rev protein, resulting in efficient export and expression of these mRNAs. Here, we show that the INS region in HIV-1 gag mRNA is a high-affinity ligand of p54nrb/PSF, a heterodimeric transcription/splicing factor. Both subunits bound INS RNA in vitro with similar affinity and specificity. Using an INS-containing subgenomic gag mRNA, we show that it specifically associated with p54nrb in vivo and that PSF inhibited its expression, acting via INS. Studying the authentic HIV-1 mRNAs produced from an infectious molecular clone, we found that PSF affected specifically the INS-containing, Rev-dependent transcripts encoding Gag-Pol and Env. Both subunits contained nuclear export and nuclear retention signals, whereas p54nrb was continuously exported from the nucleus and associated with INS-containing mRNA in the cytoplasm, suggesting its additional role at late steps of mRNA metabolism. Thus, p54nrb and PSF have properties of key factors mediating INS function and likely define a novel mRNA regulatory pathway that is hijacked by HIV-1.Many eukaryotic mRNAs are subject to regulated turnover via cis-acting signals which are recognized by trans-acting factors. The best-studied example is the cytoplasmic mRNA decay mediated by cis-acting AU-rich RNA elements and trans-acting ARE-binding proteins. Another important mechanism is nonsense-mediated mRNA decay, which serves to eliminate the transcripts that contain premature stop codons (for recent reviews, see references 17, 34, and 40).In contrast to cytoplasmic pathways, nuclear mRNA turnover is less well understood. Among the mRNAs that are subject to nuclear downregulation are the Rev-responsive element (RRE)-containing mRNAs of human immunodeficiency virus type 1 (HIV-1) (11,22,25,26,32,33,42,48,54; reviewed in references 13, 21, 27, and 47). These unspliced and nonterminally spliced transcripts need to be exported from the nucleus before completion of splicing to produce the Gag-Pol and Env proteins. This regulatory step is accomplished by the viral Rev protein, which binds to the RRE and links these transcripts to the CRM1 export receptor. In the absence of Rev, these mRNAs are further spliced to completion or degraded. However, even when devoid of splice sites, the unspliced or nonterminally spliced mRNAs are poorly expressed due to the presence of cis-acting instability elements (INS/ CRS) that are scattered throughout the gag/pol and env mRNAs (11,25,32,42,50,51,54). These elements act at several steps, impairing mRNA stability, nucleocytoplasmic transport, and translation (5,15,22,29,33,51,54), whereas Rev counteracts these defects, resulting in efficient expression. However, Rev is unable to export nonterminally spliced mRNAs that do not contain a functional INS (51), and hence, INS are an integral part of Rev regula...

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Section: Discussionmentioning

confidence: 99%

“…Several mRNA-binding proteins, including PTB/hnRNP I, hnRNP A1, and PABP1, were shown to bind specifically to such elements in vitro (2,3,9,10,41). It is thought that the INS-binding factors may divert these mRNAs from the splicing route and promote their association with Rev, enabling their export and expression.…”

mentioning

confidence: 99%

PSF Acts through the Human Immunodeficiency Virus Type 1 mRNA Instability Elements To Regulate Virus Expression

Zolotukhin

Michałowski

Bear

et al. 2003

Molecular and Cellular Biology

122

145

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“…Multiple purine-rich sequences named cis-repressive sequences or instability sequences (CRS/INS) were also identified in the genomic RNA (Schwartz et al 1992). These sequences are bound by hnRNP A1, polypyrimidine tract binding protein (PTB), poly(A)-binding protein (PABP), and polypyrimidine tract-binding protein-associated splicing factor (PSF) to regulate HIV-1 gene expression at the post-transcriptional level (Black et al 1996;Zolotukhin et al 2003). Tethering of other proteins such as the K homology splicing regulatory protein to HIV-1 RNA can also elicit RNA destabilization (Chou et al 2006).…”

Section: Introductionmentioning

confidence: 99%

Unexpected roles for UPF1 in HIV-1 RNA metabolism and translation

Ajamian

Abrahamyan²,

Milev³

et al. 2008

RNA

152

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The HIV-1 ribonucleoprotein (RNP) contains the major structural protein, pr55Gag , viral genomic RNA, as well as the host protein, Staufen1. In this report, we show that the nonsense-mediated decay (NMD) factor UPF1 is also a component of the HIV-1 RNP. We investigated the role of UPF1 in HIV-1-expressing cells. Depletion of UPF1 by siRNA resulted in a dramatic reduction in steady-state HIV-1 RNA and pr55Gag . Pr55 Gag synthesis, but not the cognate genomic RNA, was efficiently rescued by expression of an siRNA-insensitive UPF1, demonstrating that UPF1 positively influences HIV-1 RNA translatability. Conversely, overexpression of UPF1 led to a dramatic up-regulation of HIV-1 expression at the RNA and protein synthesis levels. The effects of UPF1 on HIV-1 RNA stability were observed in the nucleus and cytoplasm and required ongoing translation. We also demonstrate that the effects exerted by UPF1 on HIV-1 expression were dependent on its ATPase activity, but were separable from its role in NMD and did not require interaction with UPF2.

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“…99,102,105 Although the molecular mechanism by which INS-1 restricts HIV-1 mRNA translation initiation remains undefined, several reports suggest that host proteins are involved. [106][107][108][109] Along the same line, Brasey et al showed that the Gag ORF inhibited protein expression mediated by the HIV-1 5 0 UTR in the context of a HeLa cell line. 86 Such results were very puzzling at the time considering that the HIV-1 5 0 UTR drives the expression of Gag protein.…”

Section: Characterization Of Ires Sequencesmentioning

confidence: 90%

Translation initiation of the HIV-1 mRNA

Ohlmann¹,

Mengardi²,

López-Lastra³

2014

translation

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Translation initiation of the full-length mRNA of the human immunodeficiency virus can occur via several different mechanisms to maintain production of viral structural proteins throughout the replication cycle. HIV-1 viral protein synthesis can occur by the use of both a capdependant and IRES-driven mechanism depending on the physiological conditions of the cell and the status of the ongoing infection. For both of these mechanisms there is a need for several viral and cellular co-factors for optimal translation of the viral mRNA. In this review we will describe the mechanism used by the full-length mRNA to initiate translation highlighting the role of co-factors within this process. A particular emphasis will be given to the role of the DDX3 RNA helicase in HIV-1 mRNA translation initiation.

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Specific binding of polypyrimidine tract binding protein and hnRNP A1 to HIV-1 CRS elements

Cited by 35 publications

References 43 publications

PSF Acts through the Human Immunodeficiency Virus Type 1 mRNA Instability Elements To Regulate Virus Expression

PSF Acts through the Human Immunodeficiency Virus Type 1 mRNA Instability Elements To Regulate Virus Expression

Unexpected roles for UPF1 in HIV-1 RNA metabolism and translation

Translation initiation of the HIV-1 mRNA

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