Volume 22 Issue 7, July 2012

LRRK2 was recently identified as a major susceptibility gene for Crohn's disease (CD) by genome-wide association studies (GWAS). LRRK2 deficiency in mice confers enhanced susceptibility to experimental colitis. In this research highlight, we discuss the current understanding of LRRK2 in the context of colitis, and postulate the future directions.

Humans can be divided into roughly three groups with distinct microbial communities in their gastro-intestinal tract. The microbiota contributes to metabolic activity in the gastro-intestinal tract of the host, but what mechanisms shape the composition of the gut microbiota, and how does a person's 'enterotype' affect metabolic processes in distant organs? Flavell and colleagues shed light on these questions by revealing an important role for inflammasomes in modulating the prevalence of colitogenic species, and by demonstrating that dysbiosis influences susceptibility to non-alcoholic steatohepatitis (NASH) and other manifestations of metabolic syndrome.

Intracellular NOD-like receptor (NLR) proteins are believed to play important roles in innate immune detection or immune regulation, but only a few NLR proteins are functionally defined. Recent intensive studies, largely in vitro, on NLRC5 reveal multiple and controversial roles of this NLR protein in signaling regulation of both innate and adaptive immune responses. Using independently generated Nlrc5-deficient mice, two studies have now established the physiological function of NLRC5 in transcriptional control of MHC class I molecules despite that its role in innate immune signaling remains to be further clarified.

Tumor-associated mutations in the isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) genes result in the loss of normal catalytic activity, the production of α-ketoglutarate (α-KG), and gain of a new activity, the production of an oncometabolite, R-2-hydroxylglutarate (R-2-HG). New evidence supports previous findings that R-2-HG acts as an antagonist of α-KG to competitively inhibit the activity of multiple α-KG-dependent dioxygenases, including both histones and DNA demethylases involved in epigenetic control of gene expression and cell differentiation, and also reveals an intriguing new facet of R-2-HG in tumorigenesis.

The ORAI1 store-operated calcium channel, also known as the CRAC channel, has provided many surprises. The latest is that channel gating and ion selectivity are closely intertwined.