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.
Publication types
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Research Support, N.I.H., Intramural
MeSH terms
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Active Transport, Cell Nucleus
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Animals
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Cell Line
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Cell Nucleus / metabolism*
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Colitis / chemically induced
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Colitis / genetics
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Colitis / immunology
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Colitis / metabolism*
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Crohn Disease / genetics
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Disease Models, Animal
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Genetic Predisposition to Disease
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Humans
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Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
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Macrophage Activation / genetics
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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NFATC Transcription Factors / metabolism*
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Protein Processing, Post-Translational / immunology
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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RNA, Long Noncoding
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RNA, Untranslated / metabolism*
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Transgenes / genetics
Substances
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NFATC Transcription Factors
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NRON long non-coding RNA, mouse
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RNA, Long Noncoding
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RNA, Untranslated
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Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
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Lrrk2 protein, mouse
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Protein Serine-Threonine Kinases