The kinase LRRK2 is a regulator of the transcription factor NFAT that modulates the severity of inflammatory bowel disease
Identifieur interne : 000124 ( Main/Exploration ); précédent : 000123; suivant : 000125The kinase LRRK2 is a regulator of the transcription factor NFAT that modulates the severity of inflammatory bowel disease
Auteurs : Zhihua Liu [États-Unis] ; Jinwoo Lee [États-Unis] ; Scott Krummey [États-Unis] ; Wei Lu [États-Unis] ; Huaibin Cai [États-Unis] ; Michael J. Lenardo [États-Unis]Source :
- Nature Immunology [ 1529-2908 ] ; 2011-11.
Abstract
Leucine-rich repeat kinase 2 (LRRK2) has been identified by genome-wide association studies as being encoded by a major susceptibility gene for Crohn's disease. Here we found that LRRK2 deficiency conferred enhanced susceptibility to experimental colitis in mice. Mechanistic studies showed that LRRK2 was a potent negative regulator of the transcription factor NFAT and was a component of a complex that included the large noncoding RNA NRON (an NFAT repressor). Furthermore, the risk-associated allele encoding LRRK2 Met2397 identified by a genome-wide association study for Crohn's disease resulted in less LRRK2 protein post-translationally. Severe colitis in LRRK2-deficient mice was associated with enhanced nuclear localization of NFAT1. Thus, our study defines a new step in the control of NFAT activation that involves an immunoregulatory function of LRRK2 and has important implications for inflammatory bowel disease.
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DOI: 10.1038/ni.2113
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All Rights Reserved.</publisher><date type="published" when="2011-11">2011-11</date><biblScope unit="volume">12</biblScope><biblScope unit="issue">11</biblScope><biblScope unit="page" from="1063">1063</biblScope><biblScope unit="page" to="1070">1070</biblScope></imprint><idno type="ISSN">1529-2908</idno></series><idno type="istex">57B1F26CFC85B06F61AAB005BED0CBAD41641054</idno><idno type="DOI">10.1038/ni.2113</idno><idno type="ArticleID">ni.2113</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">1529-2908</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="eng">Leucine-rich repeat kinase 2 (LRRK2) has been identified by genome-wide association studies as being encoded by a major susceptibility gene for Crohn's disease. Here we found that LRRK2 deficiency conferred enhanced susceptibility to experimental colitis in mice. Mechanistic studies showed that LRRK2 was a potent negative regulator of the transcription factor NFAT and was a component of a complex that included the large noncoding RNA NRON (an NFAT repressor). Furthermore, the risk-associated allele encoding LRRK2 Met2397 identified by a genome-wide association study for Crohn's disease resulted in less LRRK2 protein post-translationally. Severe colitis in LRRK2-deficient mice was associated with enhanced nuclear localization of NFAT1. 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Lenardo</name><name sortKey="Lu, Wei" sort="Lu, Wei" uniqKey="Lu W" first="Wei" last="Lu">Wei Lu</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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