Redefining nucleotide-binding oligomerization domain-like receptors: from immune sentinels to multifunctional regulators

Abstract

Nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) are a large family of intracellular pattern recognition receptors primarily involved in innate immunity. Although canonical inflammasome-forming NLRs, such as NLRP3 and NLRC4, and microbial sensors, including NOD1 and NOD2, are well characterized, the functions of many other NLRs remain poorly understood. This review addresses this gap by highlighting the critical, context-dependent roles of these less-characterized NLRs beyond pathogen sensing. Here, we classify these NLRs as immune modulators, regulators of autophagy and mitophagy, tissue-specific effectors, and reproductive mediators, expanding the traditional view of NLR functions. Understanding the diverse, context-dependent roles of NLRs across biological systems is essential to fully understand their complex regulatory networks and therapeutic potential, which extends beyond classical inflammasome functions.