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

Ajamian, Lara; Abrahamyan, Levon; Milev, Miroslav P.; Ivanov, Pavel; Kulozik, Andreas E.; Gehring, Niels H.; Mouland, Andrew J.

doi:10.1261/rna.829208

Cited by 91 publications

(176 citation statements)

References 62 publications

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“…pNL4-XX was described previously (1,30), the pMrev(Ϫ) and pMtat(Ϫ) constructs were provided by the NIH AIDS Reference and Reagent Program (31), the pNL4-3rev(Ϫ) Mason-Pfizer monkey virus (MPMV) CTE was provided by Mary-Louise Hammarskjold (NCI, NIH, Frederick, MD) (32), GFP and p62(1-520)-GFP constructs were provided by Ursula Stochaj (34), and the Myc epitope-tagged hnRNP A1 expressor (pMyc-A1) was provided by Benoit Chabot (25). The bicistronic constructs used to assess HIV-1-IRES activity (pRF and pRF 104 -336) have previously been described (35,36).…”

Section: Methodsmentioning

confidence: 99%

Human Immunodeficiency Virus Type 1 (HIV-1) Induces the Cytoplasmic Retention of Heterogeneous Nuclear Ribonucleoprotein A1 by Disrupting Nuclear Import

Monette

Ajamian

López-Lastra

et al. 2009

Journal of Biological Chemistry

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143

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Human immunodeficiency virus type 1 (HIV-1) co-opts host proteins and cellular machineries to its advantage at every step of the replication cycle. Here we show that HIV-1 enhances heterogeneous nuclear ribonucleoprotein (hnRNP) A1 expression and promotes the relocalization of hnRNP A1 to the cytoplasm. The latter was dependent on the nuclear export of the unspliced viral genomic RNA (vRNA) and to alterations in the abundance and localization of the FG-repeat nuclear pore glycoprotein p62. hnRNP A1 and vRNA remain colocalized in the cytoplasm supporting a post-nuclear function during the late stages of HIV-1 replication. Consistently, we show that hnRNP A1 acts as an internal ribosomal entry site trans-acting factor up-regulating internal ribosome entry site-mediated translation initiation of the HIV-1 vRNA. The up-regulation and cytoplasmic retention of hnRNP A1 by HIV-1 would ensure abundant expression of viral structural proteins in cells infected with HIV-1.During the late stages of the HIV-1 3 replication cycle, the full-length HIV-1 viral RNA (vRNA) must be exported from the nucleus and both translated and packaged into new viral particles (1). The orchestration of these events is directed by a diversity of viral and host proteins that interact with each other and with the vRNA to form HIV-1 ribonucleoprotein (RNP) complexes that originate in the nucleus and persist in the cytoplasm (2). Investigations into the composition and functions of the HIV-1 RNP will reveal new information about innate immunity as well as identify new potential therapeutic targets (3-6).The heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) is a predominantly nuclear protein engaged in a number of cellular and viral RNPs for RNA-processing activities, including splicing regulation, nuclear export, microRNA processing, mRNA stability, telomere maintenance, and IRES-mediated translation initiation (7-12). What enables hnRNP A1 to have such broad functions in RNA metabolism is its ability to bind both nuclear and cytoplasmic RNAs (10). In addition to its well characterized role in nuclear RNA processing, hnRNP A1 binds to purine-rich sequences of mRNAs for mRNA turnover and translation (13,14). Close examination of the HIV-1 vRNA reveals many AG-and AU-rich sequences closely resembling hnRNP A1 binding motifs (15). In fact, hnRNP A1 binds to a number of sequences on the HIV-1 vRNA such as the cis-acting repressive sequences, instability elements, and exonic splicing silencer elements, and indeed, hnRNP A1 is implicated in the fate of HIV-1 RNA, including splicing regulation, nucleocytoplasmic export, and cytoplasmic stability (16 -21).Our previous work demonstrated that hnRNP A1 efficiently immunoprecipitated with the HIV-1 vRNA (22) and that siRNA-mediated knockdown of hnRNP A1 caused a dramatic decrease in HIV-1 structural protein, pr55Gag (herein termed Gag) expression and virus production with little effect on steady-state levels of the three HIV-1 RNA species (i.e. 9-, 4-, and 2-kb RNAs) (23). In this work, we show that HIV-1 ...

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Section: Methodsmentioning

confidence: 99%

Human Immunodeficiency Virus Type 1 (HIV-1) Induces the Cytoplasmic Retention of Heterogeneous Nuclear Ribonucleoprotein A1 by Disrupting Nuclear Import

Monette

Ajamian

López-Lastra

et al. 2009

Journal of Biological Chemistry

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143

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“…UPF1 is a member of the DEAD-box family of RNA helicases; and in addition to its role in NMD, it has also been implicated in several other cellular functions, such as translation stabilization, E3 ubiquitin ligation, cell cycle progression, HIV RNA metabolism, Staufen-mediated decay, telomere stability, and splicing (Kim et al 2005;Azzalin and Lingner 2006;Ajamian et al 2008;Takahashi et al 2008;Ghosh et al 2010;Chawla et al 2011;De Turris et al 2011; for review, see Imamachi et al 2012). UPF1 has been shown to associate with unspliced premRNAs in the nucleus in addition to mature mRNAs in the cytoplasm (De Turris et al 2011), and it likely binds a large variety of cellular mRNAs.…”

Section: Discussionmentioning

confidence: 99%

Nonsense-mediated decay factors are involved in the regulation of selenoprotein mRNA levels during selenium deficiency

Seyedali

Berry

2014

RNA

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Selenoproteins contain the unique amino acid selenocysteine (Sec), which is encoded by the triplet UGA. Since UGA also serves as a stop codon, it has been postulated that selenoprotein mRNAs are targeted for degradation by the nonsense-mediated mRNA decay pathway (NMD). Several reports have observed a hierarchy of selenoprotein mRNA expression when selenium (Se) is limiting, whereby the abundance of certain transcripts decline while others do not. We sought to investigate the role of NMD in this hierarchical response that selenoprotein mRNAs exhibit to environmental Se status. Selenoprotein mRNAs were categorized as being predicted sensitive or resistant to NMD based on the requirements held by the current model. About half of the selenoprotein transcriptome was predicted to be sensitive to NMD and showed significant changes in mRNA abundance in response to cellular Se status. The other half that was predicted to be resistant to NMD did not respond to Se status. RNA immunoprecipitation with essential NMD factor UPF1 revealed that the mRNAs that were the most sensitive to Se status were also the most enriched on UPF1 during Se deficiency. Furthermore, depletion of SMG1, the kinase responsible for UPF1 phosphorylation and NMD activation, abrogated the decline in transcript abundance of Se-responsive transcripts. Lastly, mRNA decay rates of Se-responsive transcripts were altered upon the addition of Se to resemble the slower decay rates of nonresponsive transcripts. Taken together, these results present novel evidence in support of a crucial role for the NMD pathway in regulating selenoprotein mRNA levels when Se is limiting.

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“…The RNAi pathway silences gene expression by inducing enzymatic degradation of targeted mRNAs [2]. In cell culture, RNAi is achieved by delivering small interfering RNAs (siRNAs).…”

Section: Identification Of Host Factors Affecting Viral Expansion In mentioning

confidence: 99%

“…A growing number of viruses including the positive-strand RNA viruses HCV [5,6,8,21,36,41,68,70,71], poliomyelitis virus [72,76], dengue virus (DENV) [81], west nile virus [18,45]; and the retroviruses HIV-1 [2,32,48,50] and foamy virus [87] depend on P-bodies and SGs components for their expansion. P-bodies and SGs are cytoplasmatic granules highly conserved from yeast to human [19,26].…”

Section: Conserved Use Of Host Factors In Viral Life Cycles: Universamentioning

confidence: 99%

Host Factors in Viral Life Cycles

Pérez‐Vilaró

Jungfleisch

Saludes

et al. 2012

Math. Model. Nat. Phenom.

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Abstract. Viruses are obligate intracellular parasites that rely on the host cell for expansion.With the development of global analyses techniques like transcriptomics, proteomics and siRNA library screening of complete cellular gene sets, a large range of host cell factors have been discovered that either support or restrict virus growth. Here we summarize some of the recent findings and focus our discussion on the hepatitis C virus and the human immunodeficiency virus, two major pathogens that threat global health. The identification of cellular proteins affecting multiple viruses points to the existence of central regulation nodes that might be exploited for both, a quantitative description of host-virus interactions within single infected cells and the development of novel, broad-spectrum antiviral drugs. Keywords and phrases:

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

Cited by 91 publications

References 62 publications

Human Immunodeficiency Virus Type 1 (HIV-1) Induces the Cytoplasmic Retention of Heterogeneous Nuclear Ribonucleoprotein A1 by Disrupting Nuclear Import

Human Immunodeficiency Virus Type 1 (HIV-1) Induces the Cytoplasmic Retention of Heterogeneous Nuclear Ribonucleoprotein A1 by Disrupting Nuclear Import

Nonsense-mediated decay factors are involved in the regulation of selenoprotein mRNA levels during selenium deficiency

Host Factors in Viral Life Cycles

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