Importance of the C-terminal domain of the human GW182 protein TNRC6C for translational repression

Zipprich, Jakob T.; Bhattacharyya, Sankar; Mathys, Hansruedi; Filipowicz, Witold

doi:10.1261/rna.1448009

Cited by 125 publications

(205 citation statements)

References 61 publications

(118 reference statements)

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“…In iLP(A -)-treated mucosa, the gene TNRC6C was upregulated, while it was downregulated in iLP. The protein encoded by TNRC6C regulates gene expression post-transcriptionally by repression of microRNAs (Zipprich et al 2009). Although there was an important number of genes in clusters 8 and 10, no great differences could be found in the gene expression profile of key inflammatory effector molecules nor clear pathways indicating likely receptors involved that could be related to the different adhesion properties of LP and LP(A -).…”

Section: Discussionmentioning

confidence: 99%

Lactobacillus paracasei and Lactobacillus plantarum strains downregulate proinflammatory genes in an ex vivo system of cultured human colonic mucosa

et al. 2012

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Significant health benefits have been demonstrated for certain probiotic strains through intervention studies; however, there is a shortage of experimental evidence relative to the mechanisms of action. Here, noninvasive experimental procedure based on a colon organ culture system has been used that, in contrast to most experimental in vitro models reported, can preserve natural immunohistochemical features of the human mucosa. This system has been used to test whether commensal lactobacilli (Lactobacillus paracasei BL23, Lactobacillus plantarum 299v and L. plantarum 299v (A -)) were able to hinder inflammation-like signals induced by phorbol 12-myristate 13-acetate (PMA)/ionomycin (IO). Whole genome microarrays have been applied to analyze expression differences, from which mRNA markers could be inferred to monitor the effect of putative probiotic strains under such conditions. Regarding the gene expression, PMA/IO treatment induced not only interleukin (IL)-2 and interferon gamma (IFN-c), as expected, but also other relevant genes related to immune response and inflammation, such as IL-17A, chemokine (C-X-C motif) ligand (CXCL) 9 and CXCL11. The ex vivo culturing did not modify the pattern of expression of those genes or others related to inflammation. Interestingly, this study demonstrated that lactobacilli downregulated those genes and triggered a global change of the transcriptional profile that indicated a clear homeostasis restoring effect and a decrease in signals produced by activated T cells.

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Section: Discussionmentioning

confidence: 99%

Lactobacillus paracasei and Lactobacillus plantarum strains downregulate proinflammatory genes in an ex vivo system of cultured human colonic mucosa

et al. 2012

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“…7 Predicted hybrids between mammalian miRNAs and their cognate mRNAs typically contain bulges and mismatches 8 and cause translational repression, which requires also function of a translational repressor TNRC6 (GW182). 9,10 AGO2 is also the "slicer"-it can mediate sequence-specific endonucleolytic cleavage of a target mRNA in the middle of the perfect basepairing between a small RNA and its cognate mRNA. 7 This sequence-specific cleavage is a hallmark of RNAi 11 but it is also found among miRNAs binding with perfect complementarity like miR-196 interaction with HoxB8 mRNA.…”

Section: Mammalian Mirna and Rnai Pathwaysmentioning

confidence: 99%

Why mouse oocytes and early embryos ignore miRNAs?

Svoboda¹

2010

RNA Biology

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Small RNA molecules regulating gene expression received a status of omnipresent master regulators of eukaryotic lives with almost supernatural powers. Mammals hold at least three mechanisms employing small RNA molecules for regulating gene expression. One of these mechanisms, the microRNA (miRNA) pathway, currently involves over a thousand of genome-encoded different miRNAs that are claimed to extend their control over more than a half of a genome. Here, I discuss how and why mouse oocytes and early embryos ignore the regulatory power of miRNAs, adding another surprising feature to the field of small RNAs.

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“…The role of the CED in repression was also previously established by others [6][7][8] . In mammals, tethering of the three regions mentioned above also represses reporter mRNA, with the major contribution being provided by the CED [9][10][11] . The mechanism by which GW182 domains repress mRNA function appears to be evolutionarily conserved, as dGW182 can repress mRNA function in mammalian cells, and human TNRC6 proteins (mammals express three counterparts of dGW182: TNRC6A, B and C) act as repressors in D. melanogaster cells 5,8,9 .…”

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confidence: 99%

miRNA repression involves GW182-mediated recruitment of CCR4–NOT through conserved W-containing motifs

Chekulaeva

Mathys

Zipprich

et al. 2011

Nat Struct Mol Biol

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324

449

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AbstractmiRNA-mediated repression in animals is dependent on the GW182 protein family. GW182 proteins are recruited to the miRNA repression complex through direct interaction with Argonaute proteins, and they function downstream to repress target mRNA. Here we demonstrate that in human and Drosophila melanogaster cells, the critical repressive features of both the N-terminal and C-terminal effector domains of GW182 proteins are Gly/Ser/Thr-Trp (G/S/TW) or Trp-Gly/ Ser/Thr (WG/S/T) motifs. These motifs, which are dispersed across both domains and act in an additive manner, function by recruiting components of the CCR 4-NOT deadenylation complex. A heterologous yeast polypeptide with engineered WG/S/T motifs acquired the ability to repress tethered mRNA and to interact with the CCR 4-NOT complex. These results identify previously unknown effector motifs functioning as important mediators of miRNA-induced silencing in both species, and they reveal that recruitment of the CCR 4-NOT complex by tryptophan-containing motifs acts downstream of GW182 to repress mRNA s, including inhibiting translation independently of deadenylation.MicroRNAs (miRNAs) are small, ~21-nt-long RNAs that post-transcriptionally regulate gene expression in eukaryotes. In animals, miRNAs bind to partially complementary sites in mRNAs, leading to translational repression and mRNA deadenylation and degradation [1][2][3][4] . miRNAs function as part of ribonucleoprotein complexes, miRNPs, with Argonaute (AGO) and GW182 family proteins being the crucial components. GW182s interact directly with AGO proteins and function downstream as effectors mediating mRNA repression. Hence, understanding the function of GW182 proteins is critical for understanding miRNAmediated repression.GW182 functional regions have been mapped in D. melanogaster and mammalian proteins. In D. melanogaster, three regions were found to repress tethered mRNA to a similar extent 5

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Importance of the C-terminal domain of the human GW182 protein TNRC6C for translational repression

Cited by 125 publications

References 61 publications

Lactobacillus paracasei and Lactobacillus plantarum strains downregulate proinflammatory genes in an ex vivo system of cultured human colonic mucosa

Lactobacillus paracasei and Lactobacillus plantarum strains downregulate proinflammatory genes in an ex vivo system of cultured human colonic mucosa

Why mouse oocytes and early embryos ignore miRNAs?

miRNA repression involves GW182-mediated recruitment of CCR4–NOT through conserved W-containing motifs

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