NLR activation takes a direct route.

For the first time there is now clear biochemical and biophysical evidence indicating that members of the nucleotide-binding domain and leucine-rich repeat containing (NLR) family can be activated as a result of direct interaction between the receptor and ligand. NLRX1 leucine-rich repeats bind to RNA; murine NAIP (NLR family, apoptosis inhibitory protein) 5 binds flagellin directly; and NOD (nucleotide-binding oligomerization domain containing) 1 and NOD2 may interact directly with fragments of peptidoglycan. It remains to be seen if NLRP3 has a specific ligand, but progress has been made in addressing its mechanism of activation, with cellular imbalances and mitochondrial dysfunction being important. This review updates our understanding of NLR activation in light of these recent advances and their impact on the NLR research.