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Nudt3 is a mRNA Decapping Enzyme That Modulates Cell Migration

ABSTRACT: The Dcp2 and Nudt16 Nudix hydrolases, are mRNA decapping enzymes that preferentially modulate stability of a subset of mRNAs. Here we report Nudt3 is a third Nudix protein that possess mRNA decapping activity in cells and is a modulator of cell migration in MCF-7 breast cancer cells. Genome-wide analysis of Nudt3 compromised cells identified increases in mRNAs involved in cell motility including integrin β6, lipocalin-2 and fibronectin. The increase in mRNA levels was dependent on Nudt3 decapping activity where integrin β6 and lipocalin-2 were modulated directly through mRNA stability, while fibronectin was indirectly controlled. Moreover, increased cell migration observed in Nudt3 depleted cells was mediated through the extracellular integrin β6 and fibronectin protein nexus. We conclude, Nudt3 is an mRNA decapping enzyme that orchestrates expression of a subset of mRNAs to modulate cell migration and further substantiates the existence of multiple decapping enzymes functioning in distinct cellular pathways in mammals.

ORGANISM(S): Homo sapiens

PROVIDER: GSE75146 | GEO | 2016/07/21

SECONDARY ACCESSION(S): PRJNA302638

REPOSITORIES: GEO

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Nudt3 is a mRNA Decapping Enzyme That Modulates Cell Migration

Project description:The Dcp2 and Nudt16 Nudix hydrolases, are mRNA decapping enzymes that preferentially modulate stability of a subset of mRNAs. Here we report Nudt3 is a third Nudix protein that possess mRNA decapping activity in cells and is a modulator of cell migration in MCF-7 breast cancer cells. Genome-wide analysis of Nudt3 compromised cells identified increases in mRNAs involved in cell motility including integrin Î²6, lipocalin-2 and fibronectin. The increase in mRNA levels was dependent on Nudt3 decapping activity where integrin Î²6 and lipocalin-2 were modulated directly through mRNA stability, while fibronectin was indirectly controlled. Moreover, increased cell migration observed in Nudt3 depleted cells was mediated through the extracellular integrin Î²6 and fibronectin protein nexus. We conclude, Nudt3 is an mRNA decapping enzyme that orchestrates expression of a subset of mRNAs to modulate cell migration and further substantiates the existence of multiple decapping enzymes functioning in distinct cellular pathways in mammals. Stably transformed MCF-7 cell lines constitutively expressing either a short hairpin RNA (shRNA) directed against Nudt3 (Nudt3KD) or a non-targeted control shRNA (ConKD) were used, with three replicate cultures used per group (n=3).

2016-07-21 | E-GEOD-75146 | biostudies-arrayexpress

An epithelial integrin regulates the amplitude of protective lung interferon responses

Project description:Integrins facilitate intercellular movement and communication. Unlike the promiscuous activities of many integrins, β6 integrin is restricted to epithelia and partners exclusively with integrin αV to modulate acute lung injury (ALI). Given that ALI is a complication of respiratory infection, we used mice lacking β6 integrin (β6 KO) to probe the role of the epithelial layer in controlling the lung microenvironment during infection. We found β6 KO mice were protected from disease caused by influenza and Sendai virus infections. They were also protected from disease caused by Streptococcus pneumoniae infection alone and after prior influenza virus infection, the co-infection representing an often-lethal condition in humans. Resistance in the absence of epithelial β6 integrin was caused by intrinsic priming of the lung microenvironment by type I interferons through a mechanism involving transforming growth factor-β regulation. Expression of β6 on epithelia suppresses the production of interferons, providing an advantage to the pathogen. Acute inhibition of β6 function may therefore provide a means to improve outcomes in lung microbial infections.

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IGDQ motogenic peptide gradient induces directional cell migration through integrin (αv)β3 activation in metastatic breast cancer

Project description:In the context of breast cancer metastasis study, we have shown in an in vitro model of cell migration that IGDQ-exposing (IsoLeu-Gly-Asp-Glutamine type I Fibronectin motif) monolayers (SAMs) on gold sustain the adhesion of MDA-MB-231 cells by triggering Focal Adhesion Kinase by activating integrins. Such tunable scaffolds are used to mimic the extracellular environment, inducing and controlling cell migration towards an anisotropic surface. The observed migratory behavior induced by the IGDQ-bearing peptide gradient along the surface suggests the presence of cell subpopulations: “stationary” or a “migratory” phenotype. We focused on the integrins α5(β1) and (αv)β3, already known to be implicated in cell migration. To this aim, a whole proteomic analysis was performed in beta 3 integrin (ITGB3) or alpha 5 integrin (ITGA5) knock-down MDA-MB-231, in order to highlight the pathways implied into the integrin-dependent cell migration. Our results showed that i) ITGB3 depletion influenced ITGA5 mRNA expression, ii) ITGB3 and ITGA5 were both necessary for IGDQ-mediated directional single cell migration, iii) integrin (αv)β3 was activated by IGDQ fibronectin type I motif and iv) co-regulation of retrograde transport of ITGB3 by ITGA5 is potentially necessary for directional IGDQ-mediated cell migration.

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The Cytoplasmic mRNA Decay Landscape of Arabidopsis Seedlings [small RNA-seq]

Project description:Cytoplasmic mRNA decay occurs through several pathways, but the contributions of these decay pathways to the degradation of specific mRNAs, and interactions between the pathways, are not well understood. We carried out a genome-wide analysis of mRNA decay rates using wild-type Arabidopsis and mutants with defects in mRNA decapping and SOV/DIS3L2. Decay rates and contributions of decapping and SOV to decay were estimated for 18,674 mRNAs using maximum likelihood modeling. Most mRNAs decayed by multiple pathways, few mRNAs degraded exclusively by mRNA decapping or SOV, and specific codon usage was linked to decay rates. Unexpected faster decay of transcripts in some genotypes was found to be independent of siRNAs; instead the data suggested an RNA buffering-like phenomenon in Arabidopsis, and that VCS (decapping) is essential for both this process and the decay of very unstable mRNAs.

2018-01-26 | GSE86360 | GEO

The Cytoplasmic mRNA Decay Landscape of Arabidopsis Seedlings [RNA-seq]

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NUDT2 loss-of-function variants are associated with a recessive neurodevelopmental disease with mental retardation, movement disorder and peripheral neuropathy

Project description:We present cases of a neurological disorder in children characterized by developmental delays in mental and motor skills, gait disturbances, and peripheral neuropathy. The disorder is associated with rare variants in the NUDT2 gene, which encodes a Nudix family mRNA decapping enzyme. The spectrum of variants includes two previously reported truncating variants and two novel variants, namely the missense c.174G>T and the in-frame deletion c.410_412del. We report that these new variants result in a marked reduction in enzymatic hydrolase activity of the encoded protein, strongly suggesting loss of function of NUDT2 as the cause of the disorder. Morover, we document that loss of function may be due to reduced enzymatic activity or impaired protein stability of NUDT2 variants. Consistent with its function in mRNA decapping, NUDT2-deficient patient fibroblasts exhibit a markedly altered transcriptome, likely due at least in part to changes in mRNA stability. Our results confirm that a reduction or loss of NUDT2-dependent mRNA decapping activity is associated with recessive neurological disease in pediatric patients. Taken together, these findings underscore the importance of a physiologically balanced mRNA processing for neuronal development and homeostasis.

2023-12-11 | GSE230789 | GEO

Global analysis of mRNA decay intermediates in Saccharomyces cerevisiae

Project description:The general pathways of eukaryotic mRNA decay occur via deadenylation followed by 3’ to 5’ degradation or decapping, although some endonuclease sites have been identified in metazoan mRNAs. To determine the role of endonucleases in mRNA degradation in Saccharomyces cerevisiae, we mapped 5’ monophosphate ends on mRNAs in wild-type and dcp2∆ xrn1∆ yeast cells, wherein mRNA endonuclease cleavage products are stabilized. This led to three important observations. First, only few mRNAs that undergo low level endonucleotyic cleavage were observed suggesting that endonucleases are not a major contributor to yeast mRNA decay. Second, independent of known decapping enzymes, we observed low levels of 5’ monophosphates on some mRNAs suggesting that an unknown mechanism can generate 5' exposed ends, although for all substrates tested Dcp2 was the primary decapping enzyme. Finally, we identified debranched lariat intermediates from intron-containing genes, demonstrating a significant discard pathway for mRNAs during the second step of pre-mRNA splicing, which is a potential new step to regulate gene expression. 5' monophosphorylated ends of poly(A) RNA from wild-type and dcp2D xrn1D strains were identified in duplicates and triplicates, respectively.

2012-06-17 | E-GEOD-33712 | biostudies-arrayexpress

Global analysis of mRNA decay intermediates in Saccharomyces cerevisiae

2012-06-17 | GSE33712 | GEO

Homo sapiens

Project description:Nudt3 is a mRNA Decapping Enzyme That Modulates Cell Migration

| PRJNA302638 | ENA

Molecular connection between the TUTase URT1 and decapping activators

Project description:Uridylation is a widespread modification destabilizing eukaryotic mRNAs. Yet, molecular mechanisms underlying TUTase-mediated mRNA degradation remain mostly unresolved. Here, we report that the Arabidopsis TUTase URT1 participates in a molecular network connecting several translational repressors/decapping activators including DECAPPING 5 (DCP5), the Arabidopsis ortholog of human LSM14 and yeast Scd6. A conserved Helical Leucine-rich Motif (HLM) within an intrinsically disordered region of URT1 binds to the LSm domain of DCP5. This interaction connects URT1 to additional decay factors like DDX6/Dhh1-like RNA helicases. The combination of in planta and in vitro analyses supports a model that explains how URT1 reduces the accumulation of oligo(A)-tailed mRNAs: first, by connecting decapping factors and second, because 3’ terminal uridines can intrinsically hinder deadenylation. Importantly, preventing the accumulation of excessively deadenylated mRNAs in Arabidopsis avoids the biogenesis of illegitimate siRNAs that silence endogenous mRNAs and perturb plant growth and development.

2020-05-29 | PXD018672 | Pride

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