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Rig-I regulates NF-?B activity through binding to Nf-?b1 3'-UTR mRNA.

ABSTRACT: Retinoic acid inducible gene I (RIG-I) senses viral RNAs and triggers innate antiviral responses through induction of type I IFNs and inflammatory cytokines. However, whether RIG-I interacts with host cellular RNA remains undetermined. Here we report that Rig-I interacts with multiple cellular mRNAs, especially Nf-?b1. Rig-I is required for NF-?B activity via regulating Nf-?b1 expression at posttranscriptional levels. It interacts with the multiple binding sites within 3'-UTR of Nf-?b1 mRNA. Further analyses reveal that three distinct tandem motifs enriched in the 3'-UTR fragments can be recognized by Rig-I. The 3'-UTR binding with Rig-I plays a critical role in normal translation of Nf-?b1 by recruiting the ribosomal proteins [ribosomal protein L13 (Rpl13) and Rpl8] and rRNAs (18S and 28S). Down-regulation of Rig-I or Rpl13 significantly reduces Nf-?b1 and 3'-UTR-mediated luciferase expression levels. These findings indicate that Rig-I functions as a positive regulator for NF-?B signaling and is involved in multiple biological processes in addition to host antivirus immunity.

SUBMITTER: Zhang HX

PROVIDER: S-EPMC3631665 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Rig-I regulates NF-κB activity through binding to Nf-κb1 3'-UTR mRNA.

Zhang Hong-Xin HX Liu Zi-Xing ZX Sun Yue-Ping YP Zhu Jiang J Lu Shun-Yuan SY Liu Xue-Song XS Huang Qiu-Hua QH Xie Yin-Yin YY Zhu Hou-Bao HB Dang Su-Ying SY Chen Hai-Feng HF Zheng Guang-Yong GY Li Yi-Xue YX Kuang Ying Y Fei Jian J Chen Sai-Juan SJ Chen Zhu Z Wang Zhu-Gang ZG

Proceedings of the National Academy of Sciences of the United States of America 20130403 16

Retinoic acid inducible gene I (RIG-I) senses viral RNAs and triggers innate antiviral responses through induction of type I IFNs and inflammatory cytokines. However, whether RIG-I interacts with host cellular RNA remains undetermined. Here we report that Rig-I interacts with multiple cellular mRNAs, especially Nf-κb1. Rig-I is required for NF-κB activity via regulating Nf-κb1 expression at posttranscriptional levels. It interacts with the multiple binding sites within 3'-UTR of Nf-κb1 mRNA. Fur ...[more]

PMID: 23553835

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Project description:RNA-binding proteins and microRNAs are potent post-transcriptional regulators of gene expression. Human transformer 2β (Tra2β) is a serine/arginine-rich-like protein splicing factor and is now implicated to have wide-ranging roles in gene expression as an RNA-binding protein. RNA immunoprecipitation (RIP) with an anti-Tra2β antibody and microarray analysis identified a subset of Tra2β-associated mRNAs in HCT116 human colon cancer cells, many of which encoded cell death-related proteins including Bcl-2 (B-cell CLL/lymphoma 2). Tra2β knockdown in HCT116 cells decreased Bcl-2 expression and induced apoptosis. Tra2β knockdown accelerated the decay of BCL2α mRNA that encodes Bcl-2 and full-length 3' UTR, while it did not affect the stability of BCL2β mRNA having a short, alternatively spliced 3' UTR different from BCL2α 3' UTR. RIP assays with anti-Tra2β and anti-Argonaute 2 antibodies, respectively, showed that Tra2β bound to BCL2α 3' UTR, and that Tra2β knockdown facilitated association of miR-204 with BCL2α 3' UTR. The consensus sequence (GAA) for Tra2β-binding lies within the miR-204-binding site of BCL2 3' UTR. Mutation of the consensus sequence canceled the binding of Tra2β to BCL2 3' UTR without disrupting miR-204-binding to BCL2 3' UTR. Transfection of an anti-miR-204 or introduction of three-point mutations into the miR-204-binding site increased BCL2 mRNA and Bcl-2 protein levels. Inversely, transfection of precursor miR-204 reduced their levels. Experiments with Tra2β-silenced or overexpressed cells revealed that Tra2β antagonized the effects of miR-204 and upregulated Bcl-2 expression. Furthermore, TRA2β mRNA expression was significantly upregulated in 22 colon cancer tissues compared with paired normal tissues and positively correlated with BCL2 mRNA expression. Tra2β knockdown in human lung adenocarcinoma cells (A549) increased their sensitivity to anticancer drugs. Taken together, our findings suggest that Tra2β regulates apoptosis by modulating Bcl-2 expression through its competition with miR-204. This novel function may have a crucial role in tumor growth.

Dataset Information

Rig-I regulates NF-?B activity through binding to Nf-?b1 3'-UTR mRNA.

Publications

Rig-I regulates NF-κB activity through binding to Nf-κb1 3'-UTR mRNA.

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