Editorial: NLR-Protein Functions in Immunity

Since Janeway (1) and Matzinger (2) put forward two distinct concepts of innate immune recognition, arguing that the driving force that initiates immune reponses is the recognition of microbial patterns or endogenous danger signals, respectively, we have acquired a tremendous wealth of knowledge of the protein families involved. Host-encoded pattern-recognition molecules (PRM) sense conservedmicrobial structures, referred to asmicrobe-associatedmolecular patterns (MAMP) or pathogen-associatedmolecular patterns (PAMP), aswell as endogenous danger-associatedmolecular patterns (DAMP). Protein families of PRM include the well-described membrane-associated toll-like receptors (TLR) (3–5) and C-type lectins (6). Beside that, the host also evolved intracellular PRM that were identified only more recently (7, 8). One important class of such intracellular PRM is the family of NOD-like receptor (NLR) proteins (9). In this research topic on “NLR-protein functions in immunity” leading experts in the field discuss various aspects of NLR biology. The proteins of the NLR family are evolutionary conserved molecules that in plants and mammals have been implicated in innate immune sensing of microbes and infection-associated physiological changes, contributing to immuneprotection of the challenged host organism through the instruction of inflammatory responses, antimicrobial defense, and adaptive immunity. Plant NLR, in contrast to mammalian NLR, recognize pathogen-derived effector molecules or the activity of these in the cytosol and can act as transcriptional regulators in the nucleus. Notably, the function of most of these proteins is conserved in phylogenetically distant species. Jacob and co-workers present current concepts on the evolution and function of NLR in plants providing an insightful comparison of the repertoire of NLR and NLR-like proteins in different plant species (10). The wiring of plant NLR to signal transduction processes, their molecular activation, and the role of sub-cellular localization are covered by a review by Qi and Innes (11). To date, our structural understanding of the mechanisms underlying activation and signaling by NLR is hampered by the intrinsic difficulty to obtain recombinant proteins suitable for structural assessment. However, functional studies and in particular evolutionary perspectives allow the acquisition of novel insights into these mechanisms. Monie and colleagues provide new insights by an evolutionary analysis of the NLR proteins Nod1 and Nod2, defining the nature of the interaction surfaces with their ligands and downstream adaptors (12). Since the first report demonstrating the involvement ofNLR in sensing bacterial components (13), their contributions to the control of infection and their impact on immune regulation is becoming increasingly understood. Opitz and co-workers summarize our understanding of the function of NLR in infectious lung diseases (14). In addition, Rosenstiel and Lipinski (15) and Flavell and colleagues (16) detail the roles of NLR in sensing intestinal bacteria in regulating intestinal immune homeostasis at steady state and during infectious challenge. Ferrero and co-workers describe how NLR drive immunity toward extracellular bacteria by recognition of MAMP in released bacterial outer-membrane vesicles (17), while Olivier and colleagues discuss the role of NLR in sensing malarial pigment hemozoin (18). Recently, the role of xenophagy in anti-bacterial host-defense is