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

Nature immunology | Oct 9, 2011

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.

Pubmed ID: 21983832 RIS Download

Mesh terms: Active Transport, Cell Nucleus | Animals | Cell Line | Cell Nucleus | Colitis | Crohn Disease | Disease Models, Animal | Genetic Predisposition to Disease | Humans | Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 | Macrophage Activation | Mice | Mice, Inbred C57BL | Mice, Knockout | NFATC Transcription Factors | Protein Processing, Post-Translational | Protein-Serine-Threonine Kinases | RNA, Long Noncoding | RNA, Untranslated | Transgenes

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Associated grants

  • Agency: Intramural NIH HHS, Id: ZIA AG000944-02
  • Agency: Intramural NIH HHS, Id: ZIA AG000944-04
  • Agency: Intramural NIH HHS, Id: ZIA AG000944-05
  • Agency: Intramural NIH HHS, Id: ZIA AG000945-02
  • Agency: Intramural NIH HHS, Id: ZIA AG000945-03
  • Agency: Intramural NIH HHS, Id: ZIA AG000944-03

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