Nature 531, 523–527 (2016)

Credit: NATURE

The kinase GCN2 is a sensor of amino acid depletion in cells and triggers the integrated stress response (ISR). Ravindran et al. set out to define its role in modulating immune responses during amino acid depletion. Using mice deficient for GCN2, the authors found that GCN2 expression both in epithelial cells and in antigen-presenting cells of the immune system was necessary to protect mice from symptoms of colitis, including gut inflammation and increased intestinal permeability in response to an inducer of inflammatory bowel disease. The authors found that the inflammation-suppressing effects of GCN2 were dependent on the downstream kinase eiF2α and occurred through a mechanism dependent on the induction of enhanced autophagy. Consistent with a role for autophagy in the control of reactive oxygen species (ROS), a well-known trigger of inflammasomes, the authors observed increased ROS in the colon and small intestine of the Gcn2 knockout mice during inflammation. Neutralization of ROS resulted in diminished inflammation. They further demonstrated enhanced inflammasome activation in Gcn2 knockout mice, and they found that genetic ablation of the inflammasome molecule Asc in the Gcn2 knockout mice negated the enhanced inflammation. Finally, amino acid deprivation could protect mice from the symptoms of colitis via a GCN2-dependent mechanism, implicating GCN2 in a function that couples sensing of amino acids with control of intestinal inflammation.