Nod-like receptors: sentinels at host membranes

Innate immune detection of danger signals and microbial motifs is achieved by distinct families of pattern recognition molecules. These include the membrane-anchored Toll-like receptors (TLRs), as well as cytosolic Nod-like receptors (NLRs) and Rig-I-like receptors (RLRs). The precise mode of NLR activation in the host cytosol remains poorly defined, as evidence of direct interaction between NLRs and danger- or microbial-associated molecular patterns remains elusive. However, a number of convergent observations now suggest that activation of some NLRs occurs at the level of host membranes or as a consequence of membrane damage. This review focuses on this emerging theme and discusses the functional consequences of innate immune sensing at the vicinity of the membrane.