The kinase LRRK2 is a regulator of the transcription factor NFAT that modulates the severity of inflammatory bowel disease.
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.
Mesh Terms:
Active Transport, Cell Nucleus, Animals, Cell Line, Cell Nucleus, Colitis, Crohn Disease, Disease Models, Animal, Genetic Predisposition to Disease, Humans, Macrophage Activation, Mice, Mice, Inbred C57BL, Mice, Knockout, NFATC Transcription Factors, Protein Processing, Post-Translational, Protein-Serine-Threonine Kinases, RNA, Long Untranslated, RNA, Untranslated, Transgenes
Active Transport, Cell Nucleus, Animals, Cell Line, Cell Nucleus, Colitis, Crohn Disease, Disease Models, Animal, Genetic Predisposition to Disease, Humans, Macrophage Activation, Mice, Mice, Inbred C57BL, Mice, Knockout, NFATC Transcription Factors, Protein Processing, Post-Translational, Protein-Serine-Threonine Kinases, RNA, Long Untranslated, RNA, Untranslated, Transgenes
Nat. Immunol.
Date: Nov. 01, 2011
PubMed ID: 21983832
View in: Pubmed Google Scholar
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