Article: The kinase LRRK2 is a regulator of the transcription factor NFAT that modulates the severity of inflammatory bowel disease

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TitleThe kinase LRRK2 is a regulator of the transcription factor NFAT that modulates the severity of inflammatory bowel disease
AuthorsLiu, Z2
Lee, J2
Krummey, S2
Lu, W2
Cai, H1
Lenardo, MJ2
Issue Date2011
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/ni
CitationNature Immunology, 2011, v. 12 n. 11, p. 1063-1070 [How to Cite?]
DOI: http://dx.doi.org/10.1038/ni.2113
AbstractLeucine-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. © 2011 Nature America, Inc. All rights reserved.
ISSN1529-2908
2011 Impact Factor: 26.008
2011 SCImago Journal Rankings: 6.226
DOIhttp://dx.doi.org/10.1038/ni.2113
ReferencesReferences in Scopus
DC Field
Value
dc.contributor.authorLiu, Z
dc.contributor.authorLee, J
dc.contributor.authorKrummey, S
dc.contributor.authorLu, W
dc.contributor.authorCai, H
dc.contributor.authorLenardo, MJ
dc.date.accessioned2012-10-08T03:20:58Z
dc.date.available2012-10-08T03:20:58Z
dc.date.issued2011
dc.description.abstractLeucine-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. © 2011 Nature America, Inc. All rights reserved.
dc.description.natureLink_to_subscribed_fulltext
dc.identifier.citationNature Immunology, 2011, v. 12 n. 11, p. 1063-1070 [How to Cite?]
DOI: http://dx.doi.org/10.1038/ni.2113
dc.identifier.citeulike9895048
dc.identifier.doihttp://dx.doi.org/10.1038/ni.2113
dc.identifier.epage1070
dc.identifier.issn1529-2908
2011 Impact Factor: 26.008
2011 SCImago Journal Rankings: 6.226
dc.identifier.issue11
dc.identifier.pmid21983832
dc.identifier.scopuseid_2-s2.0-80054933395
dc.identifier.spage1063
dc.identifier.urihttp://hdl.handle.net/10722/168577
dc.identifier.volume12
dc.languageeng
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/ni
dc.publisher.placeUnited States
dc.relation.ispartofNature Immunology
dc.relation.referencesReferences in Scopus
dc.subject.meshActive Transport, Cell Nucleus
dc.subject.meshAnimals
dc.subject.meshCell Line
dc.subject.meshCell Nucleus - Metabolism
dc.subject.meshColitis - Chemically Induced - Genetics - Immunology - Metabolism
dc.subject.meshCrohn Disease - Genetics
dc.subject.meshDisease Models, Animal
dc.subject.meshGenetic Predisposition To Disease
dc.subject.meshHumans
dc.subject.meshMacrophage Activation - Genetics
dc.subject.meshMice
dc.subject.meshMice, Inbred C57bl
dc.subject.meshMice, Knockout
dc.subject.meshNfatc Transcription Factors - Metabolism
dc.subject.meshProtein Processing, Post-Translational - Immunology
dc.subject.meshProtein-Serine-Threonine Kinases - Genetics - Metabolism
dc.subject.meshRna, Untranslated - Metabolism
dc.subject.meshTransgenes - Genetics
dc.titleThe kinase LRRK2 is a regulator of the transcription factor NFAT that modulates the severity of inflammatory bowel disease
dc.typeArticle
Author Affiliations
  1. National Institute on Aging
  2. National Institute of Allergy and Infectious Diseases