Paraspeckles modulate the intranuclear distribution of paraspeckle-associated Ctn RNA

Anantharaman, Aparna; Jadaliha, Mahdieh; Tripathi, Vidisha; Nakagawa, Shinichi; Hirose, Tetsuro; Jantsch, Michael F.; Prasanth, Supriya G.; Prasanth, Kannanganattu V.

doi:10.1038/srep34043

Cited by 22 publications

(19 citation statements)

References 45 publications

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“…In some cases, the primary function may not be to regulate editing, but they nevertheless alter ADAR binding and editing. For example, BioID recovered many of the proteins found in paraspeckles, a complex ADAR1 had previously been found to be associated with (Anantharaman et al, 2016), highlighting the power of BioID to identify nearly all proteins found in a complex. We also found proteins that are ADAR interactors but not regulators of editing.…”

Section: Discussionmentioning

confidence: 92%

Unbiased identification of trans regulators of ADAR and A-to-I RNA editing

Freund

Sapiro

et al. 2019

Preprint

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13Adenosine-to-Inosine RNA editing is catalyzed by ADAR enzymes that deaminate adenosine to 14 inosine. While many RNA editing sites are known, few trans regulators have been identified. We 15 perform BioID followed by mass-spectrometry to identify trans regulators of ADAR1 and ADAR2 16 in HeLa and M17 neuroblastoma cells. We identify known and novel ADAR-interacting proteins. 17Using ENCODE data we validate and characterize a subset of the novel interactors as global or 18 site-specific RNA editing regulators. Our set of novel trans regulators includes all four members 19 of the DZF-domain-containing family of proteins: ILF3, ILF2, STRBP, and ZFR. We show that 20 these proteins interact with each ADAR and modulate RNA editing levels. We find ILF3 is a 21 global negative regulator of editing. This work demonstrates the broad roles RNA binding 22 proteins play in regulating editing levels and establishes DZF-domain containing proteins as a 23 group of highly influential RNA editing regulators. 24 25 47 the majority of ADAR1-regulated editing sites are found in repeat regions, ADAR2 is primarily 48 responsible for editing adenosines found in non-repeat regions, particularly in the brain (Tan et 49 al., 2017). ADAR2-regulated sites in non-repetitive regions include a number of editing events 50 that alter the protein-coding sequences of neuronal RNAs, including GluR2, which encodes a 51 glutamate receptor in which RNA editing is necessary for its proper function. Further 52 demonstrating its important role in neuronal editing, dysregulation of human ADAR2 is 53 associated with multiple neurological diseases, including amyotrophic lateral sclerosis, 54 astrocytoma and transient forebrain ischemia (Slotkin and Nishikura, 2013; Tran et al., 2019). 55Maintaining RNA editing levels is critical for human health, but how RNA editing levels are 56 regulated at specific editing sites across tissues and development is poorly understood. 58While RNA sequence and structure are critical determinants of editing levels, studies querying 59 tissue-specific and developmental-stage-specific editing levels show that the level of editing at 60 the same editing site can vary greatly between individuals and tissues. These changes do not 61 always correlate with ADAR mRNA or protein expression, suggesting a complex regulation of 62 editing events by factors other than ADAR proteins (Sapiro et al., 2019; Tan et al., 2017; 63 Wahlstedt et al., 2009). Recently, an analysis of proteins with an RNA-binding domain profiled 64 by ENCODE suggested that RNA-binding proteins play a role in RNA editing regulation. Further, 65 in mammals, a small number of trans regulators of editing have been identified through 66 functional experiments (Quinones-Valdez et al., 2019). Some of these trans regulators of editing 67 are site-specific, in that they affect editing levels at only a small subset of editing sites. These 68 include RNA binding proteins such as DHX15, HNRNPA2/B1, RPS14, TDP-43, Drosha and 69 Ro60 (Garncarz et al., 2013; Quinones-Valdez ...

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Section: Discussionmentioning

confidence: 92%

Unbiased identification of trans regulators of ADAR and A-to-I RNA editing

Freund

Sapiro

et al. 2019

Preprint

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“…To evaluate whether the interaction between NONO and GSTP1 depends on paraspeckle formation, RNase digestion or si-NEAT1_2 transfection were used to destroy paraspeckle structure. 34 The results showed that destruction of paraspeckle structure suppressed GSTP1 binding to NONO or NEAT1_2 in IL-6-stimulated QGY-7703 cells ( Figure 7E, F). The data suggest that, besides trapping PRDX5 mRNA, IL-6-increased paraspeckle formation traps more GSTP1 proteins in the nucleus of HCC cells, leading to increased oxidative DNA damage.…”

Section: Prdx5 Interacts With Stat3 and Represses Stat3 Phosphorylatimentioning

confidence: 89%

“…S2B, C) to destroy the paraspeckle formation under IL-6 stimulation. 34 In Matrigel invasion assay, silencing of NEAT1_2 or NONO alone could not changed the migration of QGY-7703 and HepG2 cells, but significantly decreased IL-6-promoted migration of both cells ( Figure 3A). Furthermore, silencing of NEAT1_2 or NONO also suppressed IL-6-promoted cell cycle progression, with decreased S phase and increased G1 phase in NEAT1_2-or NONO-silenced QGY-7703 cells, and increased G1 phase and decreased G2/M phase in NEAT1_2-or NONO-silenced HepG2 cells, as compared with control cells after IL-6 stimulation ( Figure 3B).…”

Section: Paraspeckle Participates In Il-6-promoted Invasion and Survimentioning

confidence: 95%

NEAT1 paraspeckle promotes human hepatocellular carcinoma progression by strengthening IL-6/STAT3 signaling

et al. 2018

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The formation of paraspeckle, a stress-induced nuclear body, increases in response to viral infection or proinflammatory stimuli. Paraspeckle consists of lncRNA (nuclear paraspeckle assembly transcript 1, NEAT1) and protein components including NONO, SFPQ, PSPC1, etc., which are shown to be involved in viral infection and cancer. Both NEAT1 and NONO expression increase in human hepatocellular carcinoma (HCC) samples according to TCGA data. However, the role of paraspeckle in HCC progression needs further identification. IL-6 signaling is well known to contribute to HCC progression. Here we reported that IL-6 signaling increased paraspeckle formation in HCC cells. Destruction of paraspeckle formation by silencing the paraspeckle essential components NEAT1_2 or NONO could suppress IL-6induced STAT3 phosphorylation in HCC cells, and consequently repressed IL-6-promoted in vitro HCC cell invasion, cell cycle progression and survival. Mechanistically, paraspeckle promotes IL-6-induced STAT3 phosphorylation by binding and trapping peroxiredoxin-5 (PRDX5) mRNA in nucleus, decreasing protein level of PRDX5 which can directly interact with STAT3 and inhibit STAT3 phosphorylation. Besides, glutathione S-transferase P (GSTP1) protein, which inhibits DNA damage and apoptosis through its detoxification and anti-oxidation function, was also trapped within paraspeckles under IL-6 stimulation. Paraspeckle-trapping of both PRDX5 mRNA and GSTP1 protein contributes to IL-6-increased DNA damage in HCC cells. Our results demonstrate that paraspeckle can nuclear entrap the inhibitors of IL-6/ STAT3 signaling as well as DNA damage, and then strengthen the promoting effect on HCC progression by IL-6. Therefore, paraspeckle contributes to the inflammation-related HCC progression and might be a potential therapeutic target for HCC.

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“…NEAT1 is an essential component of nuclear paraspeckles [ 30 ], which contain ribonucleoprotein complexes formed around NEAT1 [ 9 ]. At present, NEAT1 is thought to be exclusive to the nucleus and mainly function as a transcriptional regulator.…”

Section: Discussionmentioning

confidence: 99%

The lncRNA NEAT1 activates Wnt/β-catenin signaling and promotes colorectal cancer progression via interacting with DDX5

et al. 2018

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BackgroundThe long noncoding RNA nuclear-enriched abundant transcript 1 (NEAT1) has been reported to be overexpressed in colorectal cancer (CRC). However, its underlying mechanisms in the progression of CRC have not been well studied.MethodsTo investigate the clinical significance of NEAT1, we analyzed its expression levels in a publicly available dataset and in 71 CRC samples from Fudan University Shanghai Cancer Center. Functional assays, including the CCK8, EdU, colony formation, wound healing, and Transwell assays, were used to determine the oncogenic role of NEAT1 in human CRC progression. Furthermore, RNA pull-down, mass spectrometry, RNA immunoprecipitation, and Dual-Luciferase Reporter Assays were used to determine the mechanism of NEAT1 in CRC progression. Animal experiments were used to determine the role of NEAT1 in CRC tumorigenicity and metastasis in vivo.ResultsNEAT1 expression was significantly upregulated in CRC tissues compared with its expression in normal tissues. Altered NEAT1 expression led to marked changes in proliferation, migration, and invasion of CRC cells both in vitro and in vivo. Mechanistically, we found that NEAT1 directly bound to the DDX5 protein, regulated its stability, and sequentially activated Wnt signaling. Our study showed that NEAT1 indirectly activated the Wnt/β-catenin signaling pathway via DDX5 and fulfilled its oncogenic functions in a DDX5-mediated manner. Clinically, concomitant NEAT1 and DDX5 protein levels negatively correlated with the overall survival and disease-free survival of CRC patients.ConclusionsOur findings indicated that NEAT1 activated Wnt signaling to promote colorectal cancer progression and metastasis. The NEAT1/DDX5/Wnt/β-catenin axis could be a potential therapeutic target of pharmacological strategies.Electronic supplementary materialThe online version of this article (10.1186/s13045-018-0656-7) contains supplementary material, which is available to authorized users.

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Paraspeckles modulate the intranuclear distribution of paraspeckle-associated Ctn RNA

Cited by 22 publications

References 45 publications

Unbiased identification of trans regulators of ADAR and A-to-I RNA editing

Unbiased identification of trans regulators of ADAR and A-to-I RNA editing

NEAT1 paraspeckle promotes human hepatocellular carcinoma progression by strengthening IL-6/STAT3 signaling

The lncRNA NEAT1 activates Wnt/β-catenin signaling and promotes colorectal cancer progression via interacting with DDX5

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