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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 volume 12, pages 1063–1070 (2011)Cite this article

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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.

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Figure 1: LRRK2 deficiency exacerbates experimental colitis in mice.
Figure 2: LRRK2 inhibits the nuclear function of NFAT1.
Figure 3: LRRK2 affects the cytoplasmic sequestration of NFAT1 but not its phosphorylation.
Figure 4: LRRK2 regulates NFAT1 by modulating the NRON complex, and degradation of LRRK2 facilitates the translocation of NFAT1 to the nucleus.
Figure 5: LRRK2 deficiency enhances NFAT1 activity in BMDMs.
Figure 6: The CD-susceptibility allele M2397 results in LRRK2 protein of lower stability.

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Acknowledgements

We thank M. Cookson (National Institute on Aging) for plasmid pCMV-2XMyc-LRRK2 expressing Myc-tagged wild-type or kinase-dead LRRK2; N. Bidere (Institut National de la Santé et de la Recherche Médicale) for luciferase constructs of NFAT and NF-κB and a renilla luciferase construct; N. Bidere, R. Germain, C. Kanellopoulou, B. Lo, A. Snow, J. Qin and H. Su for suggestions and comments; and colleagues at the Harvard Drosophila Screening Center for sharing screen results via the World Wide Web. Supported by the Intramural Research Program of the US National Institutes of Health, National Institute of Allergy and Infectious Diseases and National Institute on Aging.

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Authors and Affiliations

  1. Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland, USA

    Zhihua Liu, Jinwoo Lee, Scott Krummey, Wei Lu & Michael J Lenardo

  2. Unit of Transgenesis, Laboratory of Neurogenetics, National Institute on Aging, US National Institutes of Health, Bethesda, Maryland, USA

    Huaibin Cai

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Contributions

Z.L., J.L., S.K. and W.L. designed and did experiments; Z.L., H.C. and M.J.L. designed experiments and analyzed the data; and Z.L. and M.J.L. wrote the paper.

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Correspondence to Michael J Lenardo.

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Liu, Z., Lee, J., Krummey, S. et al. The kinase LRRK2 is a regulator of the transcription factor NFAT that modulates the severity of inflammatory bowel disease. Nat Immunol 12, 1063–1070 (2011). https://doi.org/10.1038/ni.2113

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