NLR family (NOD-like receptors)
The NLR (NOD-like receptors) family includes NOD1, NOD2, NALP1, NALP3, and IPAF receptors. In literature, they are also classified under the CLR (CARD, leucine-rich) or CATERPILLER family (the latter also includes plant protective R-proteins).
The NLR receptor molecule has a complex, modular structure. Each of its parts performs a specific task:
- C-terminal LRR domain (leucine-rich repeats): acts as a sensor that directly recognizes ligands.
- Central NOD domain: is responsible for the oligomerization (aggregation) of receptor molecules, which is critical for further signal transduction.
- N-terminal CARD domain: participates in signal generation and activation of the enzyme caspase-1. Caspase-1, in turn, is necessary for the processing of interleukin-1 (IL-1) family proinflammatory cytokines.
The main target for the LRR domain is fragments of bacterial peptidoglycan that end up in the cytosol after the bacterium has been engulfed and degraded.
- The NOD2 receptor responds to muramyl dipeptide, which is part of the cell wall of both Gram-positive and Gram-negative bacteria.
- The NOD1 receptor has a narrower specificity: it recognizes muramyl peptides with a terminal meso-diaminopimelic acid (meso-DAP), which is present exclusively in Gram-negative microorganisms.
The mechanism of action is simple: peptidoglycan binding induces oligomerization via the NOD domain and signal transduction via the CARD domain. Certain members of this family, such as NALP and IPAF, participate in the formation of a specialized complex—the inflammasome—inside which caspase-1 activation occurs.
RLR family (RIG-like receptors)
The RLR (RIG-like receptors) family specializes in viral threats. The main representatives of this group are RIG-I and MDA5 receptors. Their primary function is to recognize foreign (viral) RNA in the cytosol, which leads to the induction of synthesis of potent antiviral molecules—type I interferons.
The structure of the RLR molecule differs from NLR:
- The C-terminal RNA helicase domain is responsible for target recognition.
- The N-terminal CARD domain is responsible for signal generation and transduction.
Both receptors are capable of recognizing double-stranded viral RNA. However, RIG-I has an additional capability: it can also detect single-stranded RNA if a triphosphate group is present at its 5' end. RLR receptors are localized in various cell types of the body. There is only one important exception—plasmacytoid dendritic cells. They do not use RLRs at all, recognizing viral RNA exclusively via Toll-like receptors (TLRs).
DAI receptor and cell activation outcomes
The DAI receptor (DNA-dependent activator of IFN-regulatory factors) is another important cytosolic sensor. Unlike RLRs, it responds not to RNA, but to foreign DNA that has entered the cytoplasm. Acting as a DNA-dependent activator, it also regulates interferon production factors.
Overall, pattern recognition (PAMPs) via NLRs, RLRs, and DAI triggers the expression of a number of genes. This prepares innate immunity cells for their primary function—the efficient removal of foreign agents from the body's internal environment.
(Important distinction: cytoplasmic receptors should not be confused with soluble extracellular molecules such as collectins, pentraxins, and ficolins. The latter circulate freely outside cells and belong to humoral factors of immunity.)
Briefly: answers to topical questions
Which receptors are involved in inflammasome formation?
Intracellular receptors of the NLR family are involved in inflammasome formation. These include the following representatives:
- NOD1 (Nucleotide-oligomerizing domain) is an NLR family receptor.
- NOD2 (Nucleotide-oligomerizing domain) is an NLR family receptor.
- IPAF is an NLR family receptor.
- NALP (NALP1, NALP3) are NLR family receptors.
Which proinflammatory cytokines are processed by caspase-1 upon inflammasome activation?
Upon inflammasome activation, caspase-1 processes proinflammatory cytokines of the IL-1 family. Specifically, caspase-1 cleaves the inactive precursor of IL-1β, resulting in the formation of a mature 18 kDa cytokine that is secreted by the cell and triggers the inflammatory cascade.
What intracellular signaling pathways are triggered upon activation of NOD1 and NOD2 receptors?
Upon activation of NOD1 and NOD2 receptors following peptidoglycan binding, oligomerization involving the NOD domain and signal transduction via the CARD domain occur. Activation of these receptors leads to the activation of the transcription factor NF-κB, its translocation to the nucleus, and the production of proinflammatory cytokines and chemokines.
To remember the difference between ligands: NOD1 (contains the number 1) recognizes patterns of only ONE group of bacteria (Gram-negative). NOD2 (number 2) recognizes patterns of TWO groups (Gram-positive and Gram-negative).
Class and exam questions
Where in the cell does ligand recognition by NLR and RLR receptors take place?
In the cytosol (cytoplasm). Microbial components get there after phagocytosis and degradation, or as a result of direct viral penetration into the cell.
What are NALP and IPAF receptors needed for?
They participate in the formation of the inflammasome—a special complex in which the activation of the enzyme caspase-1 occurs, which is necessary for the processing of proinflammatory cytokines.
Which cells do not use RLRs to detect viral RNA?
Plasmacytoid dendritic cells. They use exclusively Toll-like receptors (TLRs) to recognize viral RNA.
What is the functional difference between RLRs and DAI?
Both families trigger interferon synthesis, but RLRs specialize in recognizing foreign RNA, whereas the DAI receptor detects foreign DNA in the cytosol.
What else to study on this topic
- Mechanisms of inflammasome formation and function
- Processing and functions of IL-1 family cytokines
- Synthesis and antiviral action of type I interferons
- Humoral factors of innate immunity (collectins, pentraxins, ficolins)
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