Pattern recognition receptor
From Wikipedia, the free encyclopedia
Pattern recognition receptors, or PRRs, are a class of proteins expressed by cells of the immune system to identify molecules associated with microbial pathogens. These may either be microbe-specific (e.g. lipopolysaccharide or LPS), or be associated with cellular stress (e.g. uric acid). The specific microbial structures identified by a given PRR are classified as PAMPs: pathogen-associated molecular patterns, while endogenous stress signals are classified as DAMPs (danger-associated molecular patterns). Some other PAMPs include LPS (from gram negative bacteria), peptidoglycans and lipotechoic acids (from Gram positive bacteria), mannose residues, bacterial DNA, N-formylmethionine, viral double-stranded RNA and fungal glucans.
TLRs are key elements of innate immunity, as well as being important to adaptive immunity, with PRR activation triggering a series of biological responses including cytokine secretion.
PRRs are classified according to their ligand specificity, function, localization and/or evolutionary relationships. On the basis of function, PRRs may divided into endocytic PRRs or signaling PRRs. Endocytic PRRs promote the attachment, engulfment and destruction of microorganisms by phagocytes, without relaying an intracellular signal. These PRRs recognize carbohydrates and include mannose receptors of macrophages, glucan receptors present on all phagocytes and scavenger receptors that recognize charged ligands, are found on all phagocytes and mediate removal of apoptotic cells.
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[edit] PRR Categories
[edit] Membrane-bound PRRs
[edit] Toll-like receptors
Recognition of extracellular or endosomal pathogen-associated molecular patterns is mediated by an array of transmembrane proteins known as toll-like receptors (TLRs). Toll-like receptors were discovered in Drosophila and are known to trigger a series of mechanisms leading to the synthesis and secretion of cytokines and activation other host defense programs that are crucial to the development of innate or adaptative immune responses.
At present, TLRs have been found in many species. In mammals, these receptors have been assigned numbers 1 to 11 (TLR1-TLR11). Other TLRs have been described in human and mice. Activation of TLRs induce pathways involving NFκB, MAP kinase and the secretion of pro-inflammatory cytokines as well as affect the expression of the so-called co-stimulatory molecules.
[edit] Cytoplasmic PRRs
[edit] NOD proteins
The ligands are currently known for NOD1 and NOD2. NOD1 recognizes a molecule called meso-DAP, that is a peptidoglycan constituent of only Gram negative bacteria. NOD2 proteins recognize intracellular MDP (muramyl dipeptide), which is a peptidoglycan constituent of both Gram positive and Gram negative bacteria. NODS transduce signals in the pathway of NFκB and MAP kinases via the serine-threonine kinase RIP2. NOD proteins are so named as they contain a nucleotide-binding oligomerization domain which binds nucleotide triphosphate. NODs signal via N-terminal CARD domains to activate downstream gene induction events.
[edit] NALPs
These may be considered a second category of NOD-like cytoplasmic proteins that may have a variety of functions. Current understanding suggests some of these proteins recognize endogenous or microbial molecules or stress responses and form oligomers with caspase-1 to cleave IL-1 into its active form. Like NODs, these proteins contain C-terminal leucine-rich repeats (LRRs), which appear to act as a regulatory domain and may be involved in the recognition of microbial pathogens. Like NODs, these proteins also contain a nucleotide binding site (NBS) for nucleotide triphosphates. Oligomerization with caspase-1 is mediated via N-terminal CARD or related pyrin (PYD) domains. Mutations in NALP3 are responsible for the autoinflammatory diseases familial cold autoinflammatory syndrome, Muckle–Wells syndrome and neonatal onset multisystem inflammatory disease. Ligands of NALP3 include muramyl dipeptide, bacterial DNA, ATP, toxins, and uric acid.
[edit] RNA Helicases
Intracellular recognition of viral double-stranded RNA has been shown to be mediated by a group of RNA Helicases which in turn recruit factors via twin N-terminal CARD domains to activate antiviral gene programs. Three such helicases have been described in mammals--RIG-I and MDA5, which activate antiviral signaling, and LGP2, which appears to act as a dominant-negative inhibitor.
[edit] Plant R Proteins
Plants contain a significant number of PRRs that share remarkable structural and functional similarity with those found in higher organisms such as drosophila and mammals. As can be predicted, these proteins activate host defense mechanisms in response to infection. Several characterized proteins feature NBS and LRR domains, as well as some conserved interaction domains such as the TIR. As in mammalian systems, controversy exists as to whether R proteins recognize discreet ligands via their LRRs, are activated by cellular stress, or a combination of the two.
[edit] Secreted PRRs
A number of PRRs do not remain associated with the cell that produces them. Complement receptors, collectins, pentraxin proteins such as serum amyloid and C-reactive protein, lipid transferases and peptidoglycan recognition proteins (PGRs) are all secreted proteins.
