A new eye on NLR proteins: focused on clarity or diffused by complexity?

The nucleotide-binding domain leucine-rich repeat proteins (NLRs) represent the major class of intracellular innate immune receptors in plants and animals. Understanding their functions is a major challenge in immunology. This review highlights recent efforts toward elucidating NLR functions in human and plants. We compare unconventional aspects of NLR proteins across the two kingdoms. We review recent advances describing P-loop independent activation, nuclear-cytoplasmic trafficking, oligomerization and multimerization requirements for signaling, and for expanded functions beyond pathogen recognition by several NLR proteins.