The 2–5A/RNase L/RNase L Inhibitor (RNI) Pathway Regulates Mitochondrial mRNAs Stability in Interferon α-treated H9 Cells

Roy, Florence Le; Bisbal, Catherine; Silhol, Michelle; Martinand, Camille; Lebleu, Bernard; Salehzada, Tamim

doi:10.1074/jbc.m107482200

Cited by 73 publications

(27 citation statements)

References 61 publications

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“…Accordingly, if most 2-5As were produced and active in the cytoplasmic compartment, the mitochondrial inner membrane would logically pose a hydrophobic barrier hindering the PDE12 from accessing its 2-5A substrates. Previously, an activated RNase L was also found in the mitochondria although a broad cellular distribution was observed for this enzyme [35-37]. It is therefore now possible to put forward a model with a complete 2-5A system in the mitochondria (Figure 7).…”

Section: Discussionmentioning

confidence: 91%

Mitochondrial localization of the OAS1 p46 isoform associated with a common single nucleotide polymorphism

et al. 2014

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BackgroundThe expression of 2′-5′-Oligoadenylate synthetases (OASs) is induced by type 1 Interferons (IFNs) in response to viral infection. The OAS proteins have a unique ability to produce 2′-5′ Oligoadenylates, which bind and activate the ribonuclease RNase L. The RNase L degrades cellular RNAs which in turn inhibits protein translation and induces apoptosis. Several single nucleotide polymorphisms (SNPs) in the OAS1 gene have been associated with disease. We have investigated the functional effect of two common SNPs in the OAS1 gene. The SNP rs10774671 affects splicing to one of the exons in the OAS1 gene giving rise to differential expression of the OAS1 isoforms, and the SNP rs1131454 (former rs3741981) resides in exon 3 giving rise to OAS1 isoforms with either a Glycine or a Serine at position 162 in the core OAS unit.ResultsWe have used three human cell lines with different genotypes in the OAS1 SNP rs10774671, HeLa cells with the AA genotype, HT1080 cells with AG, and Daudi cells with GG. The main OAS1 isoform expressed in Daudi and HT1080 cells was p46, and the main OAS1 isoform expressed in HeLa cells was p42. In addition, low levels of the OAS1 p52 mRNA was detected in HeLa cells and p48 mRNA in Daudi cells, and trace amounts of p44a mRNA were detected in the three cell lines treated with type 1 interferon. We show that the OAS1 p46 isoform was localized in the mitochondria in Daudi cells, whereas the OAS1 isoforms in HeLa cells were primarily localized in cytoplasmic vacuoles/lysosomes. By using recombinantly expressed OAS1 mutant proteins, we found that the OAS1 SNP rs1131454 (former rs3741981) did not affect the enzymatic OAS1 activity.ConclusionsThe SNP rs10774671 determines differential expression of the OAS1 isoforms. In Daudi and HT1080 cells the p46 isoform is the most abundantly expressed isoform associated with the G allele, whereas in HeLa cells the most abundantly expressed isoform is p42 associated with the A allele. The SNP rs1131454 (former rs3741981) does not interfere with OAS1 enzyme activity. The OAS1 p46 isoform localizes to the mitochondria, therefore a full 2-5A system can now be found in the mitochondria.

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Section: Discussionmentioning

confidence: 91%

Mitochondrial localization of the OAS1 p46 isoform associated with a common single nucleotide polymorphism

et al. 2014

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“…Moreover, mRNA of other cytokines, like IL-6, is known to be stabilized too, which leads to increased IL-6 levels [34]. There are several proteins like RNase L which controls the timing of skeletal muscle cell differentiation by orchestrating the regulation of MyoD mRNA stability [35]; poly(A)-binding protein (PABP) which protects mRNAs from ribonuclease attack [36] or A/U-rich RNA-binding protein tristetraprolin (TTP), which is a mRNA destabilizing factor which plays a role in the regulated turnover of many transcripts encoding proteins [37], which regulate the mRNA stability of various mRNAs and they could potentially be involved in this stabilization of myocardin mRNA by TNFα.…”

Section: Discussionmentioning

confidence: 99%

Dual Regulation of Myocardin Expression by Tumor Necrosis Factor-α in Vascular Smooth Muscle Cells

Singh

Zheng

2014

PLoS ONE

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De-differentiation of vascular smooth muscle cells (VSMCs) plays a critical role in the development of atherosclerosis, a chronic inflammatory disease involving various cytokines such as tumor necrosis factor-α (TNFα). Myocardin is a co-factor of serum response factor (SRF) and is considered to be the master regulator of VSMC differentiation. It binds to SRF and regulates the expression of contractile proteins in VSMCs. Myocardin is also known to inhibit VSMC proliferation by inhibiting the NF-κB pathway, whereas TNFα is known to activate the NF-κB pathway in VSMCs. NF-κB activation has also been shown to inhibit myocardin expression and smooth muscle contractile marker genes. However, it is not definitively known whether TNFα regulates the expression and activity of myocardin in VSMCs. The current study aimed to investigate the role of TNFα in regulating myocardin and VSMC function. Our studies showed that TNFα down-regulated myocardin expression and activity in cultured VSMCs by activating the NF-κB pathway, resulting in decreased VSMC contractility and increased VSMC proliferation. Surprisingly, we also found that TNFα prevented myocardin mRNA degradation, and resulted in a further significant increase in myocardin expression and activity in differentiated VSMCs. Both the NF-κB and p44/42 MAPK pathways were involved in TNFα regulation of myocardin, which further increased the contractility of VSMCs. These differential effects of TNFα on myocardin seemingly depended on whether VSMCs were in a differentiated or de-differentiated state. Taken together, our results demonstrate that TNFα differentially regulates myocardin expression and activity, which may play a key role in regulating VSMC functions.

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“…Regardless of whether the interaction is direct or indirect, RLI is a potent inhibitor of RNase-L activity. For example, RLI overexpression enhances and antisense knockdown of RLI blocks its ability to inhibit RNase-L binding to 2-5A, rRNA cleavage, destabilization of mitochondrial mRNA, and antiviral activity against HIV and EMCV (20, 38-40). …”

Section: The 2-5a Systemmentioning

confidence: 99%

“…Though generally found in the cytoplasm, RNase-L and its regulators, OAS, RLI, and 2’PDE have all been observed in the mitochondria (38, 70, 71). Several mt mRNAs, such as cytochrome b, ATPase 6, ND5, and cytochrome oxidase subunit II are downregulated or upregulated in the presence or absence respectively of RNase-L in multiple cell systems (32, 38, 72). Consistent with a role for the 2-5A system in regulating mt mRNAs, modulation of the RNase-L inhibitor RLI or the 2’PDE which degrades 2-5A also impacted the mt mRNA profile (38, 71).…”

Section: The 2-5a Systemmentioning

confidence: 99%

“…Several mt mRNAs, such as cytochrome b, ATPase 6, ND5, and cytochrome oxidase subunit II are downregulated or upregulated in the presence or absence respectively of RNase-L in multiple cell systems (32, 38, 72). Consistent with a role for the 2-5A system in regulating mt mRNAs, modulation of the RNase-L inhibitor RLI or the 2’PDE which degrades 2-5A also impacted the mt mRNA profile (38, 71). Functionally, modulation of mitochondrial gene expression is an important mechanism to regulate cellular energy production in response to cell stress or proliferative arrest.…”

Section: The 2-5a Systemmentioning

confidence: 99%

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Pathologic effects of RNase-L dysregulation in immunity and proliferative control

Hassel¹

2012

Front Biosci

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The endoribonuclease RNase-L is the terminal component of an RNA cleavage pathway that mediates antiviral, antiproliferative and immunomodulatory activities. Inactivation or dysregulation of RNase-L is associated with a compromised immune response and increased risk of cancer, accordingly its activity is tightly controlled and requires an allosteric activator, 2',5'-linked oligoadenylates, for enzymatic activity. The biological activities of RNase-L are a result of direct and indirect effects of RNA cleavage and microarray analyses have revealed that RNase-L impacts the gene expression program at multiple levels. The identification of RNase-L-regulated RNAs has provided insights into potential mechanisms by which it exerts antiproliferative, proapoptotic, senescence-inducing and innate immune activities. RNase-L protein interactors have been identified that serve regulatory functions and are implicated as alternate mechanisms of its biologic functions. Thus while the molecular details are understood for only a subset of RNase-L activities, its regulation by small molecules and critical roles in host defense and as a candidate tumor suppressor make it a promising therapeutic target.

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The 2–5A/RNase L/RNase L Inhibitor (RNI) Pathway Regulates Mitochondrial mRNAs Stability in Interferon α-treated H9 Cells

Cited by 73 publications

References 61 publications

Mitochondrial localization of the OAS1 p46 isoform associated with a common single nucleotide polymorphism

Mitochondrial localization of the OAS1 p46 isoform associated with a common single nucleotide polymorphism

Dual Regulation of Myocardin Expression by Tumor Necrosis Factor-α in Vascular Smooth Muscle Cells

Pathologic effects of RNase-L dysregulation in immunity and proliferative control

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