The kinase LRRK2 is a regulator of the transcription factor NFAT that modulates the severity of inflammatory bowel disease
Identifieur interne : 001521 ( Main/Corpus ); précédent : 001520; suivant : 001522The kinase LRRK2 is a regulator of the transcription factor NFAT that modulates the severity of inflammatory bowel disease
Auteurs : Zhihua Liu ; Jinwoo Lee ; Scott Krummey ; Wei Lu ; Huaibin Cai ; Michael J. LenardoSource :
- 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.
Url:
DOI: 10.1038/ni.2113
Links to Exploration step
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<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. 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.</div>
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<abstract 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. 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.</abstract>
<abstract type="Editorial's summary" lang="eng">The adaptor LRRK2 has been identified as a major susceptibility factor for Crohn's disease. Lenardo and colleagues show that LRRK2 negatively regulates activation of the transcription factor NFAT independently of NFAT phosphorylation.</abstract>
<note type="additional physical form">Supplementary Text and Figures : Supplementary Figures 112 [ni.2113-S1]</note>
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<identifier type="ISSN">1529-2908</identifier>
<identifier type="eISSN">1529-2916</identifier>
<part><date>2011</date>
<detail type="volume"><caption>vol.</caption>
<number>12</number>
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<detail type="issue"><caption>no.</caption>
<number>11</number>
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<extent unit="pages"><start>1063</start>
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<identifier type="DOI">10.1038/ni.2113</identifier>
<identifier type="ArticleID">ni.2113</identifier>
<accessCondition type="use and reproduction" contentType="copyright">©2011 Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.</accessCondition>
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