microRNA-induced translational control of antiviral immunity by the cap-binding protein 4EHP

Chapat, Clément; Wang, Peng; Choi, Jung‐Hyun; Li, Qian; Luo, Jun; Wiebe, Sabrina; Kim, Sung Hoon; Robichaud, Nathaniel; Karam, Isabela Fabri; Dai, David L.; Hackett, Angela P.; Lin, Rongtuan; Alain, Tommy; Yang, Long; Jafarnejad, Seyed Mehdi; Sonenberg, Nahum

doi:10.1016/j.molcel.2021.01.030

Cited by 26 publications

(46 citation statements)

References 68 publications

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“…4A-C). This alteration can be extrapolated to other miRNAs whose action relies on 4EHP, such as miR-145 or miR-34a (31,32). Recent evidence demonstrated that the 4EHP/miR-34a axis is required for the translational repression of mRNAs encoding IFN-β through targeting the 3'UTR of Ifnb1 mRNA (31).…”

Section: Discussionmentioning

confidence: 98%

“…This alteration can be extrapolated to other miRNAs whose action relies on 4EHP, such as miR-145 or miR-34a (31,32). Recent evidence demonstrated that the 4EHP/miR-34a axis is required for the translational repression of mRNAs encoding IFN-β through targeting the 3'UTR of Ifnb1 mRNA (31). Beyond miRNA, 4EHP-GIGYF2 also controls the production of TTP-targeted mRNAs that encode inflammatory cytokines such as TNF-α and IL-8 (22)(23)(24)(25)(26).…”

Section: Discussionmentioning

confidence: 99%

“…4EHP can be physically mobilized through the interaction of the GYF domain of GIGYF2 with a proline-proline-glycine-leucine (PPGL) motif in TNRC6/GW182 (29,30). At the functional level, this 4EHP/miRNA axis is required to control ERK signaling, as well as to suppress IFN-β production by effecting the miR-34a-induced translational silencing of Ifnb1 mRNA (31,32).…”

Section: Introductionmentioning

confidence: 99%

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The SARS-CoV-2 protein NSP2 impairs the microRNA-induced silencing capacity of human cells

Zou

Moch

Graille

et al. 2022

Preprint

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The coronavirus SARS-CoV-2 is the cause of the ongoing pandemic of COVID-19. Given the absence of effective treatments against SARS-CoV-2, there is an urgent need for a molecular understanding of how the virus influences the machineries of the host cell. The SARS-CoV-2 generates 16 Non-Structural Proteins (NSPs) through proteolytic cleavage of a large precursor protein. In the present study, we focused our attention on the SARS-CoV-2 protein NSP2, whose role in the viral pathogenicity is poorly understood. Recent proteomic studies shed light on the capacity of NSP2 to bind the 4EHP-GIGYF2 complex, a key factor involved in microRNA-mediated silencing of gene expression in human cells. In order to gain a better understanding of the function of NSP2, we attempted to identify the molecular basis of its interaction with 4EHP-GIGYF2. Our data demonstrate that NSP2 physically associates with the endogenous 4EHP-GIGYF2 complex in the cytoplasm. Using co-immunoprecipitation and in vitro interaction assays, we identified both 4EHP and a central segment in GIGYF2 as binding sites for NSP2. We also provide functional evidence that NSP2 impairs the function of GIGYF2 in mediating mRNA silencing using reporter-based assays, thus leading to a reduced activity of microRNAs. Altogether, these data reveal the profound impact of NSP2 on the post-transcriptional silencing of gene expression in human cells, pointing out 4EHP-GIGYF2 targeting as a possible strategy of SARS-CoV-2 to take over the silencing machinery and to suppress host defenses.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The SARS-CoV-2 protein NSP2 impairs the microRNA-induced silencing capacity of human cells

Zou

Moch

Graille

et al. 2022

Preprint

Self Cite

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“…Another 4E-BP, 4E-HP, was first shown to participate in non-canonical translational control via tethering of mRNA 5 0 and 3 0 ends [58]. Subsequent work revealed that 4E-HP participates in translational control mechanisms linked to the Ribosome-Associated Quality Control of faulty mRNAs [59], RNA decay [60], antiviral immunity [61] and development [62]. 4E-HP was also linked to hypoxia-induced repression of protein synthesis.…”

Section: Translational Control Of Gene Expressionmentioning

confidence: 99%

Translational control in neurovascular brain development

et al. 2021

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The human brain carries out complex tasks and higher functions and is crucial for organismal survival, as it senses both intrinsic and extrinsic environments. Proper brain development relies on the orchestrated development of different precursor cells, which will give rise to the plethora of mature brain cell-types. Within this process, neuronal cells develop closely to and in coordination with vascular cells (endothelial cells (ECs), pericytes) in a bilateral communication process that relies on neuronal activity, attractive or repulsive guidance cues for both cell types and on tight-regulation of gene expression. Translational control is a master regulator of the gene-expression pathway and in particular for neuronal and ECs, it can be localized in developmentally relevant (axon growth cone, endothelial tip cell) and mature compartments (synapses, axons). Herein, we will review mechanisms of translational control relevant to brain development in neurons and ECs in health and disease.

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“…Furthermore, miR-34a was found to be upregulated after RNA virus infection or IFNβ induction. Conversely, the mRNA 5′capbinding protein 4EHP was found to impede the IFNβ expression [14]. In virus-infected host cells, viruses and miRNAs interact with IFN signaling pathways.…”

Section: Introductionmentioning

confidence: 98%

Analysis of lncRNA, miRNA, and mRNA Expression Profiling in Type I IFN and Type II IFN Overexpressed in Porcine Alveolar Macrophages

Han

et al. 2021

International Journal of Genomics

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Current data is scarce regarding the function of noncoding RNAs (ncRNAs) such as microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) in the interferon- (IFN-) mediated immune response. This is a comprehensive study that analyzes the lncRNA and miRNA expression profiles of the type I IFN and type II IFN in porcine alveolar macrophages using RNA sequencing. There was a total of 152 overexpressed differentially expressed (DE) lncRNAs and 21 DE miRNAs across type I IFN and type II IFN in porcine alveolar macrophages. Subsequent lncRNA-miRNA-mRNA network construction revealed the involvement of 36 DE lncRNAs and 12 DE miRNAs. LncRNAs such as the XLOC_211306, XLOC_100516, XLOC_00695, XLOC_149196, and XLOC_014459 were expressed at a higher degree in the type I IFN group, while XLOC_222640, XLOC_047290, XLOC_147777, XLOC_162298, XLOC_220210, and XLOC_165237 were expressed at a higher degree in the type II IFN group. These lncRNAs were found to act as “sponges” for miRNAs such as miR-34a, miR-328, miR-885-3p, miR-149, miR-30c-3p, miR-30b-5p, miR-708-5p, miR-193a-5p, miR-365-5p, and miR-7. Their target genes FADS2, RPS6KA1, PIM1, and NOD1 were found to be associated with several immune-related signaling pathways including the NOD-like receptor, Jak-STAT, mTOR, and PPAR signaling pathways. These experiments provide a comprehensive profile of overexpressed noncoding RNAs in porcine alveolar macrophages, providing new insights regarding the IFN-mediated immune response.

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microRNA-induced translational control of antiviral immunity by the cap-binding protein 4EHP

Cited by 26 publications

References 68 publications

The SARS-CoV-2 protein NSP2 impairs the microRNA-induced silencing capacity of human cells

The SARS-CoV-2 protein NSP2 impairs the microRNA-induced silencing capacity of human cells

Translational control in neurovascular brain development

Analysis of lncRNA, miRNA, and mRNA Expression Profiling in Type I IFN and Type II IFN Overexpressed in Porcine Alveolar Macrophages

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