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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.

Pubmed ID: 21983832

Authors

  • Liu Z
  • Lee J
  • Krummey S
  • Lu W
  • Cai H
  • Lenardo MJ

Journal

Nature immunology

Publication Data

November 20, 2011

Associated Grants

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

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 Noncoding
  • RNA, Untranslated
  • Transgenes