Abstract
Mutations in RanBP2 (also known as Nup358), one of the main components of the cytoplasmic filaments of the nuclear pore complex, contribute to the overproduction of acute necrotizing encephalopathy (ANE1)-associated cytokines. Here we report that RanBP2 represses the translation of the interleukin 6 (IL6) mRNA, which encodes a cytokine that is aberrantly up-regulated in ANE1. Our data indicates that soon after its production, the IL6 messenger ribonucleoprotein (mRNP) recruits Argonautes bound to let-7 microRNA. After this mRNP is exported to the cytosol, RanBP2 sumoylates mRNP-associated Argonautes, thereby stabilizing them and enforcing mRNA silencing. Collectively, these results support a model whereby RanBP2 promotes an mRNP remodelling event that is critical for the miRNA-mediated suppression of clinically relevant mRNAs, such as IL6.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3' Untranslated Regions / genetics
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Argonaute Proteins / genetics*
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Argonaute Proteins / metabolism
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Cell Line, Tumor
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Eukaryotic Initiation Factors / genetics*
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Eukaryotic Initiation Factors / metabolism
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Gene Expression Regulation*
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HEK293 Cells
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Humans
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Interleukin-6 / genetics
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Interleukin-6 / metabolism
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MicroRNAs / genetics*
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MicroRNAs / metabolism
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Molecular Chaperones / genetics*
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Molecular Chaperones / metabolism
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Mutation
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Nuclear Pore Complex Proteins / genetics*
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Nuclear Pore Complex Proteins / metabolism
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Pancreatitis, Acute Necrotizing / genetics
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Pancreatitis, Acute Necrotizing / metabolism
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Protein Binding
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Sumoylation
Substances
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3' Untranslated Regions
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AGO1 protein, human
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Argonaute Proteins
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Eukaryotic Initiation Factors
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Interleukin-6
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MicroRNAs
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Molecular Chaperones
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Nuclear Pore Complex Proteins
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RNA, Messenger
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mirnlet7 microRNA, human
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ran-binding protein 2