mmu-miR-702 functions as an anti-apoptotic mirtron by mediating ATF6 inhibition in mice

Zhang, Weiguang; Chen, Lin; Dong, Qian; He, Juan; Zhao, Hua; Li, Fenglan; Li, Hui

doi:10.1016/j.gene.2013.09.005

Cited by 28 publications

(18 citation statements)

References 35 publications

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“…In addition, T-C1 also contains unique genes such as Dusp8 , a member of dual specificity phosphatases that regulate MAPK signaling, 20 and MIR702, an anti-apoptotic mirtron that binds to 3’-untranslated repeat of ATF6, which is an endoplasmic reticulum stress-associated transcription factor. 21,22 The late-responder cluster at the protein level, Pr-C2, further included known IFN-induced genes such as IFITs ISG15 , MDA5 and RSAD2 . 2 In addition, GBP5, which is reported to promote NLRP3 inflammasome assembly upon bacterial infection, 23 and CMPK2, a mitochondrial gene involved in the nucleotide salvage pathway, 24 were also part of Pr-C2 cluster, hinting at possible involvement in antiviral responses.…”

Section: Resultsmentioning

confidence: 99%

A time-resolved molecular map of the macrophage response to VSV infection

et al. 2016

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Studying the relationship between virus infection and cellular response is paradigmatic for our understanding of how perturbation changes biological systems. Immune response, in this context is a complex yet evolutionarily adapted and robust cellular change, and is experimentally amenable to molecular analysis. To visualize the full cellular response to virus infection, we performed temporal transcriptomics, proteomics, and phosphoproteomics analysis of vesicular stomatitis virus (VSV)-infected mouse macrophages. This enabled the understanding of how infection-induced changes in host gene and protein expression are coordinated with post-translational modifications by cells in time to best measure and control the infection process. The vast and complex molecular changes measured could be decomposed in a limited number of clusters within each category (transcripts, proteins, and protein phosphorylation) each with own kinetic parameter and characteristic pathways/processes, suggesting multiple regulatory options in the overall sensing and homeostatic program. Altogether, the data underscored a prevalent executive function to phosphorylation. Resolution of the molecular events affecting the RIG-I pathway, central to viral recognition, reveals that phosphorylation of the key innate immunity adaptor mitochondrial antiviral-signaling protein (MAVS) on S328/S330 is necessary for activation of type-I interferon and nuclear factor κ B (NFκB) pathways. To further understand the hierarchical relationships, we analyzed kinase–substrate relationships and found RAF1 and, to a lesser extent, ARAF to be inhibiting VSV replication and necessary for NFκB activation, and AKT2, but not AKT1, to be supporting VSV replication. Integrated analysis using the omics data revealed co-regulation of transmembrane transporters including SLC7A11, which was subsequently validated as a host factor in the VSV replication. The data sets are predicted to greatly empower future studies on the functional organization of the response of macrophages to viral challenges.

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Section: Resultsmentioning

confidence: 99%

A time-resolved molecular map of the macrophage response to VSV infection

et al. 2016

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“…For example, in alpha-1 antitrypsin deficiency, miR-199a-5p has been shown to control the expression of many key factors involved in UPR, including ATF6 [6]. In mice, miR-702 also regulates ATF6; however, the possible existence of miR-702 in the human genome is low [7]. Other miRNAs implicated in control of the UPR include miR-122 and miR-30c-3p [8,9].…”

Section: Discussionmentioning

confidence: 99%

“…Here, we extend our understanding of miR-145 and miR-494 in the context of CF bronchial epithelial cells by demonstrating their reciprocal relationship with ATF6 mRNA levels and provide evidence that miR-221 also contributes to the post-transcriptional regulation of ATF6. Regarding the expression of other miRNAs with a proven role in regulating ATF6 [6,7], neither was detected in CF and non-CF samples by in situ qRT-PCR arrays [10]. …”

Section: Discussionmentioning

confidence: 99%

miRNA-221 is elevated in cystic fibrosis airway epithelial cells and regulates expression of ATF6

et al. 2015

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BackgroundMicroRNA (miRNA) and messenger RNA (mRNA) expression differs in cystic fibrosis (CF) versus non-CF bronchial epithelium. Here, the role of miRNA in basal regulation of the transcription factor ATF6 was investigated in bronchial epithelial cells in vitro and in vivo.MethodsUsing in silico analysis, miRNAs predicted to target the 3′untranslated region (3′UTR) of the human ATF6 mRNA were identified.ResultsThree of these miRNAs, miR-145, miR-221 and miR-494, were upregulated in F508del-CFTR homozygous CFBE41o- versus non-CF 16HBE14o- bronchial epithelial cells and also in F508del-CFTR homozygous or heterozygous CF (n = 8) versus non-CF (n = 9) bronchial brushings. ATF6 was experimentally validated as a molecular target of these miRNAs through the use of a luciferase reporter vector containing the full-length 3′UTR of ATF6. Expression of ATF6 was observed to be decreased in CF both in vivo and in vitro. miR-221 was also predicted to regulate murine ATF6, and its expression was significantly increased in native airway tissues of 6-week-old βENaC-overexpressing transgenic mice with CF-like lung disease versus wild-type littermates.ConclusionsThese results implicate miR-145, miR-221 and miR-494 in the regulation of ATF6 in CF bronchial epithelium, with miR-221 demonstrating structural and functional conservation between humans and mice. The altered miRNA expression evident in CF bronchial epithelial cells can affect expression of transcriptional regulators such as ATF6.

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“…ATF6α has been best studied in the context of the heart with both ATF6α-regulated microRNAs and a micro-RNA that regulates ATF6α described under ER stress conditions [25, 26]. Both sets of microRNAs favor cell survival under ER stress conditions.…”

Section: Micrornas That Promote Adaptationmentioning

confidence: 99%

“…In an alternative approach, miR-702 was identified as a microRNA that regulates ATF6α [26]. The authors utilized isoproterenol injection in mice to show that the apoptotic stress of isoproterenol was associated with ER stress and an upregulation of miR-702.…”

Section: Micrornas That Promote Adaptationmentioning

confidence: 99%

MicroRNAs in ER Stress: Divergent Roles in Cell Fate Decisions

Malhi

2014

Curr Pathobiol Rep

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MicroRNAs are small noncoding RNAs which regulate protein expression post-transcriptionally. They respond to changes in a cells environment and can promote cell death or cell survival depending on the context. Recent studies have linked microRNAs to the unfolded protein response pathway. This pathway is activated in the endoplasmic reticulum by conditions which interfere with the normal function of the endoplasmic reticulum. The cell fate outcomes consequent to the activation of the unfolded protein response are binary, either cell survival or cell death. MicroRNAs can regulate multiple components of this pathway to tip the cell towards either fate. Interestingly, inositol requiring enzyme 1 alpha, a canonical unfolded protein response sensor and mediator, has inherent endoribonuclease activity. Recently, it has been demonstrated that it can target microRNAs in addition to its previously known targets. This review highlights key papers in this rapidly emerging field.

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mmu-miR-702 functions as an anti-apoptotic mirtron by mediating ATF6 inhibition in mice

Cited by 28 publications

References 35 publications

A time-resolved molecular map of the macrophage response to VSV infection

A time-resolved molecular map of the macrophage response to VSV infection

miRNA-221 is elevated in cystic fibrosis airway epithelial cells and regulates expression of ATF6

MicroRNAs in ER Stress: Divergent Roles in Cell Fate Decisions

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