Nod-like receptors

NOD-like receptors (NLR) are cytoplasmic proteins that recognize bacterial lipopolysaccharides and peptidoglycans. Like Toll-like receptors, they belong to the large group of pathogen recognition receptors (PPR). NOD-like receptors are an important component of innate immunity.

In contrast to other PRRs such as the Toll-like receptors, NOD-like receptors (NLRs) are not transmembrane proteins but soluble, cytoplasmic proteins. They are predominantly expressed in lymphocytes and antigen-presenting cells, but also in epithelial cells, e.g. in keratinocytes.

The >25 NLRs currently known in humans are divided into 5 groups (NLRA, NLRB, NLRC, NLRP, NLRX) (Schroder K et al. (2010):

1. NLRA (acidic transactivation domain, AD) -CITA
2. NLRB (baculovirus inhibitor of apoptosis protein repeat - BIR). The NLRB group was previously referred to as NAIP or Birc
3. NLRC (caspase activation and recruitment domain, CARD), with the two main representatives NOD1 and NOD2 as well as the NOD-like receptors NLRP3 (NLPR3 is also known as "cryopyrin"), NLRP4, NLRP5. NLRC group was previously referred to as NODs.
4. NLRP (NLRP = pyrin domain, PYD): The largest group has an N-terminal pyrin domain and is therefore referred to as "NLRP". The most important representatives are: NLRP1, NLRP2-9, NLRP11-14, NLRP10. NLRPs were previously referred to as "NALPs"
5. NLRX (functions and components are still unknown)

Biochemically, NOD-like receptors (NLR) are characterized by a three-part domain structure:

Centrally located is the nucleotide binding oligomerization domain (NOD), C-terminal are leucine-rich repeats (LRR). The effector domains CARD, pyrin or BIR are bound N-terminal.

PAMPs (also MAMPs-microbial/pathogen associated molecular pattern) are recognized and bound via the leucine-rich docking sites. The N-terminal domain defines which signalling pathways are induced downstream when the receptors are activated.

NOD-like receptors activate an inflammatory response through the expression of antimicrobial peptides. Furthermore, NOD-like receptors induce processes such as apoptosis via mechanisms that have not yet been clearly clarified.

In principle, the NLRs can be divided into two main groups with regard to their function: the NLRC group with the two main representatives NOD1 and NOD2 and the inflammasome-activating NLRs with their main representatives NLRPs.

NOD1 and NOD2 recognize components of peptidoglycan, which form the main scaffold of the bacterial cell wall. After the Toll-like receptors, they thus represent a second cytoplasmic barrier for the elimination of bacteria that have escaped the recognition of cell membrane-bound receptors.

In analogy to the apoptosomes, which activate the apoptosis-inducing caspases (caspase-9, -8, -2), the NLR complexes are called "inflammasomes", as they activate the inflammatory caspases-1, -4 and -5 in human cells (Martinon F et al. (2002). Such inflammasome complexes are formed in myeloid cells of the immune system, such as macrophages and dendritic cells, but can also be found in keratinocytes (Schroder K et al. 2010). Activation of the inflammasome leads to the expression of caspases that convert inactive interleukin-1beta and interleukin-18 into their biologically active form.

The physiological significance of NLR becomes apparent in clinical pictures that have arisen due to genetic mutations(autoinflammatory diseases) and that are characterized by defined, chronic inflammatory or autoimmunological processes.

1. Franchi L et al. (2008) Intracellular NOD-like receptors in innate immunity, infection and disease.Cell Microbiol 10:1-8.

2. Inohara N et al. (2003) Nods: Intracellular proteins involved in inflammation and apoptosis. Nat Rev Immunol 3: 371-382

3. Martinon F (2008). Detection of immune danger signals by NALP3. J Leukoc Biol 83: 507-11

4. Rathinam VA et al. (2010) The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses. Nat Immunol 11:395-402.

5. Schröder K et al. (2010) The inflammasomes. Cell 140:821-832.