Dephosphorylation of the nuclear factor of activated T cells (NFAT) transcription factor is regulated by an RNA-protein scaffold complex

Sharma, Sonia; Findlay, Gregory M.; Bandukwala, Hozefa S.; Oberdoerffer, Shalini; Baust, Beate; Li, Zhigang; Schmidt, Valentina A.; Hogan, Patrick G.; Sacks, David B.; Rao, Anjana

doi:10.1073/pnas.1019711108

Cited by 253 publications

(241 citation statements)

References 34 publications

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“…The experiments were carried out with HeLa cells and Jurkat T cells obtained from ATCC; HeLa NFAT1-GFP cells (43,44); and TMEM110 −/− HEK293 cell lines and their parental HEK293 cells (23). Expression plasmids encoded STIM1, STIM2, TMEM110, and TMEM110(Δ211-294), tagged as indicated; Clover-Ist2 (490-946); and the ER markers RFP-ER, DsRed-ER, and blue fluorescent protein (BFP)-ER.…”

Section: Methodsmentioning

confidence: 99%

TMEM110 regulates the maintenance and remodeling of mammalian ER–plasma membrane junctions competent for STIM–ORAI signaling

Quintana

Vangipurapu

Farber-Katz

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The stromal interaction molecule (STIM)–ORAI calcium release-activated calcium modulator (ORAI) pathway controls store-dependent calcium entry, a major mechanism of physiological calcium signaling in mammalian cells. The core elements of the pathway are the regulatory protein STIM1, located in the endoplasmic reticulum (ER) membrane, the calcium channel ORAI1 in the plasma membrane, and sites of close contact between the ER and the plasma membrane that permit the two proteins to interact. Research on calcium signaling has centered on STIM1, ORAI1, and a few proteins that directly modulate STIM–ORAI function. However, little is known about proteins that organize ER–plasma membrane junctions for STIM–ORAI-dependent calcium signaling. Here, we report that an ER-resident membrane protein identified in a previous genome-wide RNAi screen, transmembrane protein 110 (TMEM110), regulates the long-term maintenance of ER–plasma membrane junctions and the short-term physiological remodeling of the junctions during store-dependent calcium signaling.

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Section: Methodsmentioning

confidence: 99%

TMEM110 regulates the maintenance and remodeling of mammalian ER–plasma membrane junctions competent for STIM–ORAI signaling

Quintana

Vangipurapu

Farber-Katz

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…IQGAP proteins (IQGAP1, 2, and 3) are widely expressed proteins with the ability to regulate very diverse biological processes, including cytoskeleton dynamics, vesicle trafficking, cell proliferation, intracellular signaling, and TF activity (34). Most importantly, T lymphocytes from IQGAP1-deficient mice displayed increased production of cytokines, and both IQGAP1 and IQGAP2 were shown to interact with the long noncoding RNA NRON (noncoding RNA repressor of NFAT), known to interfere with nuclear import of the TF NFAT (37,38). We therefore hypothesized that altered expression of Iqgap2 could explain, at least in part, the various phenotypes observed in activated mast cells lacking Dnmt3a, including increased cytokine production and degranulation.…”

Section: Dysregulated Dna Methylation Activity Leads To Increased Masmentioning

confidence: 99%

“…Because IQGAP1 and IQGAP2 were shown to interfere with nuclear translocation of NFAT (37,38), and NFAT is required for efficient transactivation of cytokine genes in mast cells (39,40), we assessed whether nuclear translocation of NFAT was somehow affected in KO cells, due to the altered expression of Iqgap family members. First, we transduced WT and KO cells to stably express comparable levels of a reporter NFAT-GFP fusion protein (41), and then we assessed nuclear translocation of the reporter protein with a fluorescence microscope (Fig.…”

Section: Dysregulated Dna Methylation Activity Leads To Increased Masmentioning

confidence: 99%

Dnmt3a restrains mast cell inflammatory responses

Leoni

Montagner

Rinaldi

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

108

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DNA methylation and specifically the DNA methyltransferase enzyme DNMT3A are involved in the pathogenesis of a variety of hematological diseases and in regulating the function of immune cells. Although altered DNA methylation patterns and mutations in DNMT3A correlate with mast cell proliferative disorders in humans, the role of DNA methylation in mast cell biology is not understood. By using mast cells lacking Dnmt3a, we found that this enzyme is involved in restraining mast cell responses to acute and chronic stimuli, both in vitro and in vivo. The exacerbated mast cell responses observed in the absence of Dnmt3a were recapitulated or enhanced by treatment with the demethylating agent 5-aza-2′-deoxycytidine as well as by down-modulation of Dnmt1 expression, further supporting the role of DNA methylation in regulating mast cell activation. Mechanistically, these effects were in part mediated by the dysregulated expression of the scaffold protein IQGAP2, which is characterized by the ability to regulate a wide variety of biological processes. Altogether, our data demonstrate that DNMT3A and DNA methylation are key modulators of mast cell responsiveness to acute and chronic stimulation.DNA methylation | epigenetics | inflammation | mast cells

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“…Some lncRNAs, such as 7SK, can directly affect the loading and activity of general TFs and to further affect the production of mRNAs[54]. Moreover, another lncRNA, NRON, can directly serve as either co-factors or inhibitors to regulate the activity of nuclear factor of activated T cells (NFAT) proteins which manipulate gene expression in many cell types[55]. In this study, using TRANSFAC, 75 TFs were predicted to have the potential to combine with NONMMUT011061, including some TFs associated with the immune response and some important pathways, such as IRF, MAF, HSF, GATA sequence and Myc (Figure 8).…”

Section: Discussionmentioning

confidence: 99%

Deep sequencing of the mouse lung transcriptome reveals distinct long non-coding RNAs expression associated with the high virulence of H5N1 avian influenza virus in mice

Hu¹,

Hu²,

Wang³

et al. 2018

Virulence

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Long non-coding RNAs (lncRNAs) play multiple key regulatory roles in various biological processes. However, their function in influenza A virus (IAV) pathogenicity remains largely unexplored. Here, using next generation sequencing, we systemically compared the whole-transcriptome response of the mouse lung infected with either the highly pathogenic (A/Chicken/Jiangsu/k0402/2010, CK10) or the nonpathogenic (A/Goose/Jiangsu/k0403/2010, GS10) H5N1 virus. A total of 126 significantly differentially expressed (SDE) lncRNAs from three replicates were identified to be associated with the high virulence of CK10, whereas 94 SDE lncRNAs were related with GS10. Functional category analysis suggested that the SDE lncRNAs-coexpressed mRNAs regulated by CK10 were highly related with aberrant and uncontrolled inflammatory responses. Further canonical pathway analysis also confirmed that these targets were highly enriched for inflammatory-related pathways. Moreover, 9 lncRNAs and 17 lncRNAs-coexpressed mRNAs associated with a large number of targeted genes were successfully verified by qRT-PCR. One targeted lncRNA (NONMMUT011061) that was markedly activated and correlated with a great number of mRNAs was selected for further in-depth analysis, including predication of transcription factors, potential interacting proteins, genomic location, coding ability and construction of the secondary structure. More importantly, NONMMUT011061 was also distinctively stimulated during the highly pathogenic H5N8 virus infection in mice, suggesting a potential universal role of NONMMUT011061 in the pathogenesis of different H5 IAV. Altogether, these results provide a subset of lncRNAs that might play important roles in the pathogenesis of influenza virus and add the lncRNAs to the vast repertoire of host factors utilized by IAV for infection and persistence.

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Dephosphorylation of the nuclear factor of activated T cells (NFAT) transcription factor is regulated by an RNA-protein scaffold complex

Cited by 253 publications

References 34 publications

TMEM110 regulates the maintenance and remodeling of mammalian ER–plasma membrane junctions competent for STIM–ORAI signaling

TMEM110 regulates the maintenance and remodeling of mammalian ER–plasma membrane junctions competent for STIM–ORAI signaling

Dnmt3a restrains mast cell inflammatory responses

Deep sequencing of the mouse lung transcriptome reveals distinct long non-coding RNAs expression associated with the high virulence of H5N1 avian influenza virus in mice

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