Editors' ChoiceImmunology

Holding Back NFAT

Science Signaling  25 Oct 2011:
Vol. 4, Issue 196, pp. ec295
DOI: 10.1126/scisignal.4196ec295

Genome-wide studies have associated many gene loci with susceptibility to inflammatory bowel disease (IBD); however, how the products of many of these genes contribute to IBD is unclear (see commentary by Jabri and Barreiro). One example is the gene that encodes leucine-rich repeat kinase 2 (LRRK2), which is highly associated with Crohn’s disease (CD). Liu et al. found that mice deficient in LRRK2 (Lrrk2–/– mice) were more susceptible to colitis induced by dextran sulfate sodium (DSS) than were wild-type mice. Experiments involving transfer of bone marrow cells from wild-type or Lrrk2–/– mice to recipient mice before exposure to DSS showed that deficiency in Lrrk2 in hematopoietic cells was sufficient to exacerbate colitis. An RNA interference screen in Drosophila melanogaster suggested that the Drosophila ortholog of LRRK2 suppressed the activity of the transcription factor nuclear factor of activated T cells (NFAT). Transfection of human embryonic kidney (HEK) 293 cells with plasmid encoding LRRK2 resulted in decreased NFAT reporter activity compared with that in cells transfected with control plasmid. Increased abundance of LRRK2 correlated with the decreased nuclear accumulation of NFAT in stimulated cells, and this effect did not require the kinase activity of LRRK2. Immunoprecipitations showed that LRRK2 enhanced the association between NFAT1 and components of a protein complex that also included the large noncoding RNA (NRON), which represses NFAT activity by retaining it in the cytosol. Stimulation of bone marrow–derived macrophages (BMDMs) from Lrrk2–/– mice with zymosan (a constituent of the cell wall of Candida) produced greater quantities of proinflammatory cytokines than did stimulation of wild-type BMDMs. One polymorphism of human LRRK2 associated with CD results in the substitution of Thr2397 with methionine (the “M2397 allele”). Liu et al. found that the M2397 variant of LRRK2 was less stable than the T2397 variant and had a decreased inhibitory effect on NFAT activity. Together, these data suggest that LRRK2 acts to retain NFAT in the cytosol and that decreases in LRRK2 abundance caused by gene polymorphisms associated with IBD lead to enhanced NFAT activity and increased production of proinflammatory cytokines.

Z. Liu, J. Lee, S. Krummey, W. Lu, H. Cai, M. J. Lenardo, 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). [PubMed]

B. Jabri, L. B. Barreiro, Don’t move: LRRK2 arrests NFAT in the cytoplasm. Nat. Immunol. 12, 1029–1030 (2011). [PubMed]