Nuclear Import of Cytoplasmic Poly(A) Binding Protein Restricts Gene Expression via Hyperadenylation and Nuclear Retention of mRNA

ABSTRACT Poly(A) tail length is emerging as an important marker of mRNA fate, where deviations from the canonical length can signal degradation or nuclear retention of transcripts. Pathways regulating polyadenylation thus have the potential to broadly influence gene expression. Here we demonstrate that accumulation of cytoplasmic poly(A) binding protein (PABPC) in the nucleus, which can occur during viral infection or other forms of cellular stress, causes mRNA hyperadenylation and nuclear accumulation of poly(A) RNA. This inhibits gene expression but does not affect mRNA stability. Unexpectedly, PABPC-induced hyperadenylation can occur independently of mRNA 3′-end processing yet requires the canonical mRNA poly(A) polymerase II. We find that nuclear PABPC-induced hyperadenylation is triggered by multiple divergent viral factors, suggesting that altering the subcellular localization of PABPC may be a commonly used mechanism to regulate cellular gene expression in a polyadenylation-linked manner.

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Inhibition of Transcription Induces Phosphorylation of YB-1 at Ser102 and Its Accumulation in the Nucleus

Cells ◽

10.3390/cells9010104 ◽

2019 ◽

Vol 9 (1) ◽

pp. 104 ◽

Cited By ~ 2

Author(s):

Dmitry A. Kretov ◽

Daria A. Mordovkina ◽

Irina A. Eliseeva ◽

Dmitry N. Lyabin ◽

Dmitry N. Polyakov ◽

...

Keyword(s):

Gene Expression ◽

Rna Polymerase Ii ◽

Nuclear Localization ◽

Kinase Activity ◽

Binding Protein ◽

Dna Binding Protein ◽

Regulatory Mechanisms ◽

Nuclear Accumulation ◽

Nuclear Retention ◽

Post Translational Modifications

The Y-box binding protein 1 (YB-1) is an RNA/DNA-binding protein regulating gene expression in the cytoplasm and the nucleus. Although mostly cytoplasmic, YB-1 accumulates in the nucleus under stress conditions. Its nuclear localization is associated with aggressiveness and multidrug resistance of cancer cells, which makes the understanding of the regulatory mechanisms of YB-1 subcellular distribution essential. Here, we report that inhibition of RNA polymerase II (RNAPII) activity results in the nuclear accumulation of YB-1 accompanied by its phosphorylation at Ser102. The inhibition of kinase activity reduces YB-1 phosphorylation and its accumulation in the nucleus. The presence of RNA in the nucleus is shown to be required for the nuclear retention of YB-1. Thus, the subcellular localization of YB-1 depends on its post-translational modifications (PTMs) and intracellular RNA distribution.

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Faculty Opinions recommendation of Nuclear import of cytoplasmic poly(A) binding protein restricts gene expression via hyperadenylation and nuclear retention of mRNA.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.5725957.5708055 ◽

2010 ◽

Author(s):

Megerditch Kiledjian

Keyword(s):

Gene Expression ◽

Nuclear Import ◽

Binding Protein ◽

Nuclear Retention

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Regulation of Nuclear Gamma Interferon Gene Expression by Interleukin 12 (IL-12) and IL-2 Represents a Novel Form of Posttranscriptional Control

Molecular and Cellular Biology ◽

10.1128/mcb.22.6.1742-1753.2002 ◽

2002 ◽

Vol 22 (6) ◽

pp. 1742-1753 ◽

Cited By ~ 39

Author(s):

Deborah L. Hodge ◽

Alfredo Martinez ◽

John G. Julias ◽

Lynn S. Taylor ◽

Howard A. Young

Keyword(s):

Gene Expression ◽

Nk Cells ◽

Cellular Response ◽

Gamma Interferon ◽

Nuclear Accumulation ◽

Interleukin 12 ◽

Mrna Accumulation ◽

Nuclear Retention ◽

Posttranscriptional Control ◽

Ifn Γ

ABSTRACT Posttranscriptional control of gamma interferon (IFN-γ) gene expression has not been extensively studied and is poorly understood. Our work describes a posttranscriptional mechanism that modulates IFN-γ mRNA expression in stimulated natural killer (NK) cells through nuclear retention of the IFN-γ mRNA. This is evidenced by the elevated and sustained nuclear accumulation of both precursor and processed IFN-γ mRNAs in NK cells stimulated with interleukin-12 (IL-12). The elevated nuclear mRNA accumulation persists long after transcriptional activity has subsided and the rate of cytoplasmic IFN-γ mRNA accumulation has dropped. The IL-12-induced nuclear retention of the IFN-γ mRNA prevails until a secondary cytokine stimulus is received. The secondary stimulus, which is initiated by IL-2, mediates transcription-independent movement of the nuclear IFN-γ mRNA. Concurrent with the nucleocytoplasmic movement of the IFN-γ mRNA, we have observed increases in the amount of processed nuclear IFN-γ mRNA that are greater than that seen for the unprocessed IFN-γ mRNA. The increase in processed IFN-γ mRNA appears to be due to increased mRNA stability which then promotes increased nucleocytoplasmic shuttling of the mature IFN-γ mRNA. These data support a model whereby mobilization of nuclear IFN-γ mRNA stores allows NK cells to rapidly and robustly respond to secondary cytokine activators in a transcription-independent manner, thus shortening the time for overall cellular response to inflammatory signals.

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