Chk2-dependent HuR phosphorylation regulates occludin mRNA translation and epithelial barrier function
Occludin is a transmembrane tight junction (TJ) protein that plays an important role in TJ assembly and regulation of the epithelial barrier function, but the mechanisms underlying its post-transcriptional regulation are unknown. The RNA-binding protein HuR modulates the stability and translation of...
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| Veröffentlicht in: | Nucleic acids research 2011-10, Vol.39 (19), p.8472-8487 |
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| creator | Yu, Ting-Xi Wang, Peng-Yuan Rao, Jaladanki N. Zou, Tongtong Liu, Lan Xiao, Lan Gorospe, Myriam Wang, Jian-Ying |
| description | Occludin is a transmembrane tight junction (TJ) protein that plays an important role in TJ assembly and regulation of the epithelial barrier function, but the mechanisms underlying its post-transcriptional regulation are unknown. The RNA-binding protein HuR modulates the stability and translation of many target mRNAs. Here, we investigated the role of HuR in the regulation of occludin expression and therefore in the intestinal epithelial barrier function. HuR bound the 3′-untranslated region of the occludin mRNA and enhanced occludin translation. HuR association with the occludin mRNA depended on Chk2-dependent HuR phosphorylation. Reduced HuR phosphorylation by Chk2 silencing or by reduction of Chk2 through polyamine depletion decreased HuR-binding to the occludin mRNA and repressed occludin translation, whereas Chk2 overexpression enhanced (HuR/occludin mRNA) association and stimulated occludin expression. In mice exposed to septic stress induced by cecal ligation and puncture, Chk2 levels in the intestinal mucosa decreased, associated with an inhibition of occludin expression and gut barrier dysfunction. These results indicate that HuR regulates occludin mRNA translation through Chk2-dependent HuR phosphorylation and that this influence is crucial for maintenance of the epithelial barrier integrity in the intestinal tract. |
| doi_str_mv | 10.1093/nar/gkr567 |
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The RNA-binding protein HuR modulates the stability and translation of many target mRNAs. Here, we investigated the role of HuR in the regulation of occludin expression and therefore in the intestinal epithelial barrier function. HuR bound the 3′-untranslated region of the occludin mRNA and enhanced occludin translation. HuR association with the occludin mRNA depended on Chk2-dependent HuR phosphorylation. Reduced HuR phosphorylation by Chk2 silencing or by reduction of Chk2 through polyamine depletion decreased HuR-binding to the occludin mRNA and repressed occludin translation, whereas Chk2 overexpression enhanced (HuR/occludin mRNA) association and stimulated occludin expression. In mice exposed to septic stress induced by cecal ligation and puncture, Chk2 levels in the intestinal mucosa decreased, associated with an inhibition of occludin expression and gut barrier dysfunction. These results indicate that HuR regulates occludin mRNA translation through Chk2-dependent HuR phosphorylation and that this influence is crucial for maintenance of the epithelial barrier integrity in the intestinal tract.</description><identifier>ISSN: 0305-1048</identifier><identifier>EISSN: 1362-4962</identifier><identifier>DOI: 10.1093/nar/gkr567</identifier><identifier>PMID: 21745814</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>3' Untranslated Regions ; Animals ; Cell Membrane Permeability ; Cells, Cultured ; Checkpoint Kinase 2 ; ELAV Proteins - metabolism ; Gene Expression Regulation ; Intestinal Mucosa - metabolism ; Male ; Membrane Proteins - biosynthesis ; Membrane Proteins - genetics ; Mice ; Molecular Biology ; Occludin ; Phosphorylation ; Polyamines - metabolism ; Protein Biosynthesis ; Protein-Serine-Threonine Kinases - metabolism ; Rats ; RNA, Messenger - metabolism ; Sepsis - enzymology ; Sepsis - genetics</subject><ispartof>Nucleic acids research, 2011-10, Vol.39 (19), p.8472-8487</ispartof><rights>The Author(s) 2011. Published by Oxford University Press. 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c439t-44eb35cd499e57d8048db24a508c154a26dda41cc6fcaf5b44def3ffb3adaea13</citedby><cites>FETCH-LOGICAL-c439t-44eb35cd499e57d8048db24a508c154a26dda41cc6fcaf5b44def3ffb3adaea13</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3201881/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3201881/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,1598,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21745814$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yu, Ting-Xi</creatorcontrib><creatorcontrib>Wang, Peng-Yuan</creatorcontrib><creatorcontrib>Rao, Jaladanki N.</creatorcontrib><creatorcontrib>Zou, Tongtong</creatorcontrib><creatorcontrib>Liu, Lan</creatorcontrib><creatorcontrib>Xiao, Lan</creatorcontrib><creatorcontrib>Gorospe, Myriam</creatorcontrib><creatorcontrib>Wang, Jian-Ying</creatorcontrib><title>Chk2-dependent HuR phosphorylation regulates occludin mRNA translation and epithelial barrier function</title><title>Nucleic acids research</title><addtitle>Nucleic Acids Res</addtitle><description>Occludin is a transmembrane tight junction (TJ) protein that plays an important role in TJ assembly and regulation of the epithelial barrier function, but the mechanisms underlying its post-transcriptional regulation are unknown. The RNA-binding protein HuR modulates the stability and translation of many target mRNAs. Here, we investigated the role of HuR in the regulation of occludin expression and therefore in the intestinal epithelial barrier function. HuR bound the 3′-untranslated region of the occludin mRNA and enhanced occludin translation. HuR association with the occludin mRNA depended on Chk2-dependent HuR phosphorylation. Reduced HuR phosphorylation by Chk2 silencing or by reduction of Chk2 through polyamine depletion decreased HuR-binding to the occludin mRNA and repressed occludin translation, whereas Chk2 overexpression enhanced (HuR/occludin mRNA) association and stimulated occludin expression. In mice exposed to septic stress induced by cecal ligation and puncture, Chk2 levels in the intestinal mucosa decreased, associated with an inhibition of occludin expression and gut barrier dysfunction. These results indicate that HuR regulates occludin mRNA translation through Chk2-dependent HuR phosphorylation and that this influence is crucial for maintenance of the epithelial barrier integrity in the intestinal tract.</description><subject>3' Untranslated Regions</subject><subject>Animals</subject><subject>Cell Membrane Permeability</subject><subject>Cells, Cultured</subject><subject>Checkpoint Kinase 2</subject><subject>ELAV Proteins - metabolism</subject><subject>Gene Expression Regulation</subject><subject>Intestinal Mucosa - metabolism</subject><subject>Male</subject><subject>Membrane Proteins - biosynthesis</subject><subject>Membrane Proteins - genetics</subject><subject>Mice</subject><subject>Molecular Biology</subject><subject>Occludin</subject><subject>Phosphorylation</subject><subject>Polyamines - metabolism</subject><subject>Protein Biosynthesis</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>Rats</subject><subject>RNA, Messenger - metabolism</subject><subject>Sepsis - enzymology</subject><subject>Sepsis - genetics</subject><issn>0305-1048</issn><issn>1362-4962</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>TOX</sourceid><sourceid>EIF</sourceid><recordid>eNqFkV9rFDEUxYModq2--AEkLyIIY5NJMn9ehLKoFYqFUp_DneRmN3Y2GZOZQr99s-xa9KU-XO6F--NwDoeQt5x94qwXZwHS2eY2qaZ9RlZcNHUl-6Z-TlZMMFVxJrsT8irnX4xxyZV8SU5q3krVcbkibr29rSuLEwaLYaYXyzWdtjGXSfcjzD4GmnCzlBMzjcaMi_WB7q5_nNM5QchHBoKlOPl5i6OHkQ6QksdE3RLM_v-avHAwZnxz3Kfk59cvN-uL6vLq2_f1-WVlpOjnSkochDJW9j2q1nbFuh1qCYp1pjiHurEWJDemcQacGqS06IRzgwALCFycks8H3WkZdmhNiZRg1FPyO0j3OoLX_36C3-pNvNOiZrzr9gIfjgIp_l4wz3rns8FxhIBxybrnHWsEa7v_k4y1rWprUciPB9KkmHNC9-iHM71vUJcG9aHBAr_7O8Ej-qeyArw_AHGZnhJ6AJ2SqJM</recordid><startdate>20111001</startdate><enddate>20111001</enddate><creator>Yu, Ting-Xi</creator><creator>Wang, Peng-Yuan</creator><creator>Rao, Jaladanki N.</creator><creator>Zou, Tongtong</creator><creator>Liu, Lan</creator><creator>Xiao, Lan</creator><creator>Gorospe, Myriam</creator><creator>Wang, Jian-Ying</creator><general>Oxford University Press</general><scope>TOX</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>20111001</creationdate><title>Chk2-dependent HuR phosphorylation regulates occludin mRNA translation and epithelial barrier function</title><author>Yu, Ting-Xi ; Wang, Peng-Yuan ; Rao, Jaladanki N. ; Zou, Tongtong ; Liu, Lan ; Xiao, Lan ; Gorospe, Myriam ; Wang, Jian-Ying</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c439t-44eb35cd499e57d8048db24a508c154a26dda41cc6fcaf5b44def3ffb3adaea13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>3' Untranslated Regions</topic><topic>Animals</topic><topic>Cell Membrane Permeability</topic><topic>Cells, Cultured</topic><topic>Checkpoint Kinase 2</topic><topic>ELAV Proteins - metabolism</topic><topic>Gene Expression Regulation</topic><topic>Intestinal Mucosa - metabolism</topic><topic>Male</topic><topic>Membrane Proteins - biosynthesis</topic><topic>Membrane Proteins - genetics</topic><topic>Mice</topic><topic>Molecular Biology</topic><topic>Occludin</topic><topic>Phosphorylation</topic><topic>Polyamines - metabolism</topic><topic>Protein Biosynthesis</topic><topic>Protein-Serine-Threonine Kinases - metabolism</topic><topic>Rats</topic><topic>RNA, Messenger - metabolism</topic><topic>Sepsis - enzymology</topic><topic>Sepsis - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yu, Ting-Xi</creatorcontrib><creatorcontrib>Wang, Peng-Yuan</creatorcontrib><creatorcontrib>Rao, Jaladanki N.</creatorcontrib><creatorcontrib>Zou, Tongtong</creatorcontrib><creatorcontrib>Liu, Lan</creatorcontrib><creatorcontrib>Xiao, Lan</creatorcontrib><creatorcontrib>Gorospe, Myriam</creatorcontrib><creatorcontrib>Wang, Jian-Ying</creatorcontrib><collection>Oxford Journals Open Access Collection</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Nucleic acids research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yu, Ting-Xi</au><au>Wang, Peng-Yuan</au><au>Rao, Jaladanki N.</au><au>Zou, Tongtong</au><au>Liu, Lan</au><au>Xiao, Lan</au><au>Gorospe, Myriam</au><au>Wang, Jian-Ying</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Chk2-dependent HuR phosphorylation regulates occludin mRNA translation and epithelial barrier function</atitle><jtitle>Nucleic acids research</jtitle><addtitle>Nucleic Acids Res</addtitle><date>2011-10-01</date><risdate>2011</risdate><volume>39</volume><issue>19</issue><spage>8472</spage><epage>8487</epage><pages>8472-8487</pages><issn>0305-1048</issn><eissn>1362-4962</eissn><abstract>Occludin is a transmembrane tight junction (TJ) protein that plays an important role in TJ assembly and regulation of the epithelial barrier function, but the mechanisms underlying its post-transcriptional regulation are unknown. The RNA-binding protein HuR modulates the stability and translation of many target mRNAs. Here, we investigated the role of HuR in the regulation of occludin expression and therefore in the intestinal epithelial barrier function. HuR bound the 3′-untranslated region of the occludin mRNA and enhanced occludin translation. HuR association with the occludin mRNA depended on Chk2-dependent HuR phosphorylation. Reduced HuR phosphorylation by Chk2 silencing or by reduction of Chk2 through polyamine depletion decreased HuR-binding to the occludin mRNA and repressed occludin translation, whereas Chk2 overexpression enhanced (HuR/occludin mRNA) association and stimulated occludin expression. In mice exposed to septic stress induced by cecal ligation and puncture, Chk2 levels in the intestinal mucosa decreased, associated with an inhibition of occludin expression and gut barrier dysfunction. These results indicate that HuR regulates occludin mRNA translation through Chk2-dependent HuR phosphorylation and that this influence is crucial for maintenance of the epithelial barrier integrity in the intestinal tract.</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>21745814</pmid><doi>10.1093/nar/gkr567</doi><tpages>16</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 3' Untranslated Regions Animals Cell Membrane Permeability Cells, Cultured Checkpoint Kinase 2 ELAV Proteins - metabolism Gene Expression Regulation Intestinal Mucosa - metabolism Male Membrane Proteins - biosynthesis Membrane Proteins - genetics Mice Molecular Biology Occludin Phosphorylation Polyamines - metabolism Protein Biosynthesis Protein-Serine-Threonine Kinases - metabolism Rats RNA, Messenger - metabolism Sepsis - enzymology Sepsis - genetics |
| title | Chk2-dependent HuR phosphorylation regulates occludin mRNA translation and epithelial barrier function |
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