HUMAN NOD-LIKE RECEPTORS CAN ASSEMBLE INTO LARGE MULTIPROTEIN COMPLEXES AFTER RECOGNIZING INFECTIOUS SIGNALS

Tetè G, Giordano D, Cordas D, Schmitthenner J. Human nod-like receptors can assemble into large multiprotein complexes after recognizing infectious signals.  International Journal of Infection. 2026;10(2):50-53.

G. Tetè^1*, D. Giordano², D. Cordas³ and J. Schmitthenner⁴

¹ Department of Human Sciences, “Sustainable Blue Economy and One Health”, UNIDAV, Telematic University, Chieti, Italy;
² Department of Neurosciences, Mental Health and Sensory Organs, Sant’ Andrea Hospital, Sapienza University of Rome, Italy;
³ “Grigiore T. Popa” Medical University, Iasi, Romania;
⁴ Pneumology Department, Halle Hospital, Germany.

*Correspondence to:
Dr. Giulia Tetè,
Department of Human Sciences, “Sustainable Blue Economy and One Health”,
UNIDAV, Telematic University,
Chieti, Torrevecchia Teatina 66100, Italy.
e-mail: tetegiulia92@gmail.com

Received: 27 May, 2026 Accepted: 17 July, 2026

ISSN 3103-6678 [online] Copyright 2026 © by Biolife Publisher This publication and/or article is for individual use only and may not be further reproduced without written permission from the copyright holder. Unauthorized reproduction may result in financial and other penalties. Disclosure: all authors report no conflicts of interest relevant to this article.

ABSTRACT

NOD-like receptors (NLRs) are cytoplasmic receptors of the innate immune system that recognize pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), and other signals of infection or cellular damage, activating immune responses such as the formation of inflammasomes or the NF-κB pathway. NLRs are intracellular receptors composed of an N-terminal domain, a central NACHT domain that allows oligomerization, and a C-terminal Leucine-Rich Repeats (LRR) domain involved in signal recognition and autoinhibition. They recognize PAMPs and DAMPs after initial pathogen recognition by Toll-like receptors (TLRs), with NOD1 detecting peptidoglycan fragments from Gram-negative bacteria and NOD2 recognizing the muramyl dipeptide found in most bacteria. NOD1 and NOD2 work together with the NLR family pyrin domain containing 3 (NLRP3) inflammasome to regulate the inflammatory response; mutations in these receptors are associated with inflammatory and autoimmune diseases, such as Crohn’s disease, as well as other conditions such as asthma, sarcoidosis, Behçet’s disease, and diabetes. NLR family CARD domain-containing protein 4 (NLRC4) is a receptor of the NLR family that, together with NLR family apoptosis inhibitory proteins (NAIPs), recognizes bacterial components such as flagellin and type III secretion system (T3SS) proteins, forming the inflammasome. Activation of the NLRC4 inflammasome induces caspase-1, which promotes the maturation of the cytokines IL-1β and IL-18 and pyroptosis, a form of inflammatory cell death. During bacterial infections, NOD1 and NOD2 activate NF-κB, increasing the synthesis of inflammatory precursors, while NLRC4 provides the secondary signal required for their maturation and cytokine release.

KEYWORDS: NOD-like receptor, inflammasome, NOD1, NOD2, infection, innate immunity

INTRODUCTION

Receptors of the NOD-like receptor (NLR) family play a crucial role in recognizing infectious and danger signals (1).  In addition to evolving in animals, NLRs have also evolved in the plant world, where they exhibit significant differences (2). In plants, NLRs recognize pathogen effector proteins and can assemble into resistosomes, large protein machines that form inside plant cells to fight off infections from microorganisms, while in animals, they recognize intracellular pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) and function primarily as signaling platforms, forming inflammasomes or activating pathways such as NF-κB (3).

In humans, NLRs are innate immune receptors present in the cell cytoplasm that recognize the presence of pathogenic microorganisms or cellular damage (4). Some widely studied NLRs include the NLR family pyrin domain containing 3 (NLRP3) and NLR family CARD domain-containing protein 4 (NLRC4) inflammasomes.

NOD-LIKE RECEPTORS IN INFECTION   

NLRs identify pathogens after they have been recognized extracellularly by Toll-like receptors (TLRs) or endosomes (5). NLRs possess a structure composed of an N-terminal effector domain, which can be a caspase recruitment domain (CARD) or Pyrin Domain (PYD), which serves to recruit other proteins involved in cell signaling (6). The central NACHT domain binds ATP and allows the receptor to oligomerize upon activation (5). The C-terminal Leucine-Rich Repeats (LRR) domain is involved in signal recognition and receptor autoinhibition (5). NLRs primarily recognize PAMPs but they can also recognize DAMPs released by damaged cells. The most studied proteins in the NLR family are NOD1 and NOD2.

NOD1 recognizes peptidoglycan fragments from Gram-negative bacteria, while NOD2 recognizes muramyl dipeptide, present in the cell wall of almost all bacteria (7). Some diseases, such as Crohn’s disease, are associated with a genetic mutation in NOD2 which causes a defect in the protein; It no longer recognizes bacteria correctly, instead mistakenly attacking the intestine, causing swelling and pain, characteristic signs of Crohn’s disease (8). NOD2 is a cellular receptor that detects bacteria, while the inflammasome (NLRP3) is a group of proteins that creates inflammation (5). NOD2 works together with NLRP3 to protect the body by regulating the immune response against microorganisms (9). The NLRP3 inflammasome is a protein complex that creates inflammation and is activated by various stimuli such as ATP, ionic changes, bacterial toxins, and microorganisms (10).

NOD1 is also a sensor protein that acts as an “alarm” in the innate immune system, and its genetic mutations are associated with various inflammatory and autoimmune diseases. The NOD1 protein gene interacts with metabolic mechanisms and is therefore also being studied for its role in insulin resistance and diabetes management. Major diseases linked to NOD1 include Behçet’s disease, sarcoidosis, inflammatory bowel disease (Crohn’s disease), Helicobacter pylori infections, and asthma (11,12).

NLRC4 belongs to the same family as NOD1 and 2, and possesses several key ligands, such as components of the type III secretion system and bacterial flagellin (13). Additionally, while the signaling pathway for NOD1 and 2 is NF-κB and MAPK, for NLRC4 it is the inflammasome, resulting in the activation of caspase-1, maturation of IL-1β and IL-18, and pyroptosis (via Gasdermin D) (14). Therefore, NLRC4 does not primarily activate NF-κB, but forms an inflammasome together with NLR family apoptosis inhibitory proteins (NAIPs), which recognize flagellin or proteins of the bacterial type III secretion system (13).

NAIPs are also innate immune proteins belonging to the NLR family. Their main function is not to directly form the inflammasome, but rather to recognize specific bacterial components and activate NLRC4 (15). NAIPs are important because when a bacterium invades the cell cytoplasm, they recognize bacterial signaling molecules (PAMPs) such as flagellin and type III secretion system proteins (T3SS) (13). Once NAIP binds to the ligand, it changes conformation and recruits molecules that assemble to form the NLRC4 inflammasome (14). Therefore, NAIP is the “sentinel” receptor that detects specific bacterial components in the cytoplasm and triggers activation of the NLRC4 inflammasome, essential for a rapid response against intracellular microorganisms (13).

The inflammasome subsequently activates caspase-1, which induces the maturation of IL-1β and IL-18 and pyroptosis, a form of inflammatory cell death (16,17). Thus, NOD1, NOD2, and NLRC4 cooperate during bacterial infection (18,19). NOD1 and NOD2 act as primers and activate NF-κB, increasing the synthesis of pro-IL-1β, pro-IL-18, and inflammasome components (17,20). NLRC4, on the other hand, provides the second signal, assembling the inflammasome and activating caspase-1, allowing the maturation and release of IL-1β and IL-18, cytokines that are involved in inflammation (18,21).

CONCLUSIONS

NLRs are cytoplasmic sensors of the innate immune system that allow cells to detect infections or intracellular damage and rapidly activate inflammatory and defensive responses. They are critical for innate immunity and coordinate the inflammatory response through the activation of signalling pathways such as NF-κB and the formation of inflammasomes. Specifically, NOD1 and NOD2 detect bacterial components and initiate the immune response, while NLRC4, in collaboration with NAIP proteins, activates the inflammasome, promoting the maturation of IL-1β and IL-18 and pyroptosis. Alterations in these receptors impair the regulation of the immune response and are associated with various inflammatory, autoimmune, and metabolic diseases.

Conflict of interest

The authors declare that they have no conflict of interest.

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