Rosetta Stone of NLR Innate Immunity

Abstract

The formation of NLR inflammasomes is a central step in the initiation of the innate immune response. Two recent publications describe the structure of the NAIP2-NLRC4 inflammasome and derive an elegant model of NLR inflammasome formation, whereby binding of the pathogen-molecule-bound NLR NAIP2 to NLRC4 leads to the activation of NLRC4 and initiation of self-propagating NLRC4 inflammasome formation.

Keywords: cryo-EM; inflammasome; inflammation; innate immunity.

Figure 1. Schematic model of PrgJ-NAIP2-NLRC4 inflammasome formation

(A) Binding of the Salmonella Typhimurium protein PrgJ (orange) to NAIP2 [5] (grey; model based on NLRC4 monomer from PDB ID 3JBL [9]) leads to formation of an initial nucleating (or ‘catalytic’) basic surface (blue) on NAIP2. This basic surface can bind to an acidic ‘receptor’ surface (red) on the autoinhibited NLRC4 (cyan; PDB ID 4KXF [4]). (B) Binding of PrgJ-NAIP2 to NLRC4 induces a conformational change in NLRC4 and opening of the leucine-rich repeat (LRR) domain, which in turn exposes a newly formed nucleating (basic) surface (blue) on the NLRC4 NOD (nucleotide-binding and oligomerization domain). This basic surface can now further interact with the acidic surface of other autoinhibited NLRC4 molecules, leading to self-propagating oligomerization of NLRC4 (inflammasome formation). (C) Fully formed PrgJ-NAIP2-NLRC4 inflammasome (based on PDB ID 3JBL [9]).