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Save changes Cite Insert Pattern recognition receptor Pattern recognition receptors (PRRs)[1] play a crucial role in the proper function of the innate immune system. PRRs are germline-encoded host sensors, which detect molecules typical for the pathogens[2]. They are proteins expressed by cells of the innate immune system, such as dendritic cells and macrophages[3], to identify two classes of molecules: pathogen-associated molecular patterns (PAMPs), which are associated with microbial pathogens, and damage-associated molecular patterns (DAMPs), which are associated with components of host's cells that are released during cell damage or death. They are also called primitive pattern recognition receptors because they evolved before other parts of the immune system, particularly before adaptive immunity. PRRs also mediate the initiation of antigen-specific adaptive immune response and release of inflammatory cytokines[2][4]

Molecules recognized The microbe-specific molecules that are recognized by a given PRR are called pathogen-associated molecular patterns (PAMPs) and include bacterial carbohydrates (such as lipopolysaccharide or LPS, mannose), nucleic acids (such as bacterial or viral DNA or RNA), bacterial peptides (flagellin, microtubule elongation factors), peptidoglycans and lipoteichoic acids (from Gram-positive bacteria), N-formylmethionine, lipoproteins and fungal glucans and chitin.

Endogenous stress signals are called damage-associated molecular patterns (DAMPs) and include uric acid and extracellular ATP, among many other compounds[2].

Classification There are several subgroups of PRRs. They are classified according to their ligand specificity, function, localization and/or evolutionary relationships. Based on their localization, PRRs may be divided into membrane-bound PRRs and cytoplasmic PRRs.

Membrane-bound PRRs include Toll like receptors (TLRs) and C-type lectin receptors (CLRs). Cytoplasmic PRRs include NOD-like receptors (NLRs) and RIG-I-like receptors (RLRs). PRR types and localization Membrane-bound PRRs Receptor kinases PRRs were first discovered in plants.[5] Since that time many plant PRRs have been predicted by genomic analysis (370 in rice; 47 in Arabidopsis). Unlike animal PRRs, which associated with intracellular kinases via adaptor proteins (see non-RD kinases below), plant PRRs are composed of an extracellular domain, transmembrane domain, juxtamembrane domain and intracellular kinase domain as part of a single protein.

Toll-like receptors (TLR) Recognition of extracellular or endosomal pathogen-associated molecular patterns is mediated by transmembrane proteins known as toll-like receptors (TLRs).[6] TLRs share a typical structural motif, the leucine rich repeats (LRR), which give them their specific appearance and are also responsible for TLR functionality[7]. Toll-like receptors were first discovered in Drosophila and trigger the synthesis and secretion of cytokines and activation of other host defense programs that are necessary for both innate or adaptive immune responses. 10 functional members of the TLR family have been described in humans so far[8]. Studies have been conducted on TLR11 as well, and it has been shown that it recognizes flagellin and profilin-like proteins in mice[9]. Nonetheless, TLR11 is only a pseudogene in humans without direct function or functional protein expression. Each of the TLR has been shown to interact with a specific PAMP[4][10][11].

The TLR signaling mechanism TLRs tend to dimerize, TLR4 forms homodimers, and TLR6 can dimerize with either TLR1 or TLR2. [10] Interaction of TLRs with their specific PAMP is mediated through either MyD88- dependent pathway and triggers the signaling through NF-κB and the MAP kinase pathway and therefore the secretion of pro-inflammatory cytokines and co-stimulatory molecules or TRIF - dependent signaling pathway[2][4][10]. MyD88 - dependent pathway is induced by various PAMPs stimulating the TLRs on macrophages and dendritic cells. MyD88 attracts the IRAK4 molecule, IRAK4 recruits IRAK1 and IRAK2 to form a signaling complex. The signaling complex reacts with TRAF6 which leads to TAK1 activation and consequently the induction of inflammatory cytokines.The TRIF-dependent pathway is induced by macrophages and DCs after TLR3 and TLR4 stimulation.[2] Molecules released following TLR activation signal to other cells of the immune system making TLRs key elements of innate immunity and adaptive immunity.[2][12][13]

C-type lectin receptors (CLR) Many different cells are involved in the innate immune system, starting from cells as complex as immature dendritic cells to cells as small as platelets, express a myriad of CLRs which shape innate immunity by virtue of their pattern recognition ability.[14] Most classes of human pathogens are covered by CLRs: e.g. among external or infectious pathogens mannose is the recognition motif for many viruses, fungi and mycobacteria; similarly fucose for certain bacteria and helminths; and glucans are present on mycobacteria and fungi. In addition, many of acquired nonself surfaces e.g. carcinoembryonic/oncofetal type neoantigens carrying "internal danger source"/"self turned nonself" type pathogen pattern are also identified and destroyed (e.g. by complement fixation or other cytotoxic attacks) or sequestered (phagocytosed or ensheathed) by the immune system by virtue of the CLRs. The name lectin is also a bit misleading because the family includes proteins with at least one C-type lectin domain (CTLD) which is a specific type of carbohydrate recognition domain. CTLD is a ligand binding motif found in more than 1000 known proteins (more than 100 in humans) and the ligands are often not sugars.[15] If and when the ligand is sugar they need Ca2+ – hence the name "C-type", but many of them don't even have a known sugar ligand thus despite carrying a lectin type fold structure, some of them are technically not "lectin" in function.

CLRs are often endocytic receptors but may be also signaling as well, and depending on the ligand their signaling and trafficking fate might be different. They may have direct signaling including MAP kinase and NFkB activation or may act indirectly by modulating TLRs. CLRs are a very big category and includes soluble PRRs as well (see at the end of this article) that serve many important immune functions.

Membrane receptor CLRs are broadly grouped into:

Group I CLRs: The mannose receptors The mannose receptor (MR) is a PRR primarily present on the surface of macrophages and dendritic cells. The MR belongs to the multilectin receptor protein group and, like the TLRs, provides a link between innate and adaptive immunity.[16] It recognizes and binds to repeated mannose units on the surfaces of infectious agents and its activation triggers endocytosis and phagocytosis of the microbe via the complement system. Specifically, mannose binding triggers recruitment of MBL-associated serine proteases (MASPs). The serine proteases activate themselves in a cascade, amplifying the immune response: MBL interacts with C4, binding the C4b subunit and releasing C4a into the bloodstream; similarly, binding of C2 causes release of C2b. Together, MBL, C4b and C2a are known as the C3 convertase. C3 is cleaved into its a and b subunits, and C3b binds the convertase. These together are called the C5 convertase. Similarly again, C5b is bound and C5a is released. C5b recruits C6, C7, C8 and multiple C9s. C5, C6, C7, C8 and C9 form the membrane attack complex (MAC).

Group II CLRs: asialoglycoprotein receptor family This is another large superfamily of CLRs that includes molecules like

The classic asialoglycoprotein receptor macrophage galactose-type lectin (MGL) DC-SIGN (CLEC4L) Langerin (CLEC4K) Myeloid DAP12‑associating lectin (MDL)‑1 (CLEC5A) DC‑associated C‑type lectin 1 (Dectin1) subfamily which includes dectin 1/CLEC7A DNGR1/CLEC9A Myeloid C‑type lectin‑like receptor (MICL) (CLEC12A) CLEC2 (also called CLEC1B)- the platelet activation receptor for podoplanin on lymphatic endothelial cells and invading front of some carcinomas. CLEC12B DC immunoreceptor (DCIR) subfamily which includes: DCIR/CLEC4A Dectin 2/CLEC6A Blood DC antigen 2 (BDCA2) ( CLEC4C) Mincle i.e. macrophage‑inducible C‑type lectin (CLEC4E) The nomenclature (mannose versus asialoglycoprotein) is a bit misleading as these the asialoglycoprotein receptors are not necessarily galactose (one of the commonest outer residues of asialo-glycoprotein) specific receptors and even many of this family members can also bind to mannose after which the other group is named.

Cytoplasmic PRRs NOD-like receptors (NLR) For more details, see NOD-like receptor.

The NOD-like receptors (NLRs) are cytoplasmic proteins that regulate inflammatory and apoptotic responses. Approximately 20 of these proteins have been found in the mammalian genome and include two major subfamilies called NODs and NALPs, the MHC Class II transactivator (CIITA), IPAF, BIRC1, and other molecules.[17] This family of proteins is greatly expanded in plants, and constitutes a core component of plant immune systems.[18] Some of these proteins recognize endogenous or microbial molecules or stress responses and form oligomers that, in animals, activate inflammatory caspases (e.g. caspase 1) causing cleavage and activation of important inflammatory cytokines such as IL-1, and/or activate the NF-κB signaling pathway to induce production of inflammatory molecules. The NLR family is known under several different names, including the CATERPILLER (or CLR) or NOD-LRR family.[17][19]

Insert paragraph NODs

The ligands are currently known for NOD1 and NOD2. NOD1 recognizes a molecule called meso-DAP, which is a peptidoglycan constituent only of 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 NF-κB and MAP kinases via the serine-threonine kinase called RIP2. NOD proteins are so named because they contain a nucleotide-binding oligomerization domain which binds nucleoside triphosphate. NODs signal via N-terminal CARD domains to activate downstream gene induction events, and interact with microbial molecules by means of a C-terminal leucine-rich repeat (LRR) region.[20]

Insert paragraph Insert paragraph Insert paragraph NALPs

Like NODs, these proteins contain C-terminal LRRs, which appear to act as a regulatory domain and may be involved in the recognition of microbial pathogens. Also like NODs, these proteins also contain a nucleotide binding site (NBS) for nucleoside triphosphates. Interaction with other proteins (e.g. the adaptor molecule ASC) is mediated via N-terminal pyrin (PYD) domain. There are 14 members of this subfamily in humans (called NALP1 to NALP14). Mutations in NALP3 are responsible for the autoinflammatory diseases familial cold autoinflammatory syndrome, Muckle–Wells syndrome and neonatal onset multisystem inflammatory disease. Activators of NALP3 include muramyl dipeptide, bacterial DNA, ATP, toxins, double stranded RNA, paramyxoviruses and uric acid crystals. Although these specific molecules have been shown to activate NALP3, it remains unclear whether this is due to direct binding or due to cellular stress induced by these agents.

Insert paragraph Insert paragraph Insert paragraph Other NLRs

Other NLRs such as IPAF and NAIP5/Birc1e have also been shown to activate caspase-1 in response to Salmonella and Legionella.

Insert paragraph RIG-I-like receptors (RLR) Further information: RIG-I-like receptor Three helicases have so far been described as part of the RLRs: RIG-I and MDA5 (recognizing 5'triphosphate-RNA and dsRNA, respectively), which activate antiviral signaling, and LGP2, which appears to act as a dominant-negative inhibitor. RLRs initiate the release of inflammatory cytokines and type I interferon (IFN I)[2]. RLRs, are RNA helicases, which have been shown to participate in intracellular recognition of viral double-stranded (ds) and single stranded RNA which recruit factors via twin N-terminal CARD domains to activate antiviral gene programs. It has been suggested that the main antiviral program induced by RLR is based on ATPase activity[21].

RIG-I and Mda5-mediated signalling pathway. Plant PRRs Plants contain a significant number of PRRs that share remarkable structural and functional similarity with drosophila TOLL and mammalian TLRs. The first PRR identified in plants or animals was the Xa21 protein, conferring resistance to the Gram-negative bacterial pathogen Xanthomonas oryzae pv. oryzae.[5][22] Since that time two other plants PRRs, Arabidopsis FLS2 (flagellin) and EFR (elongation factor Tu receptor)have been isolated.[23] The corresponding PAMPs for FLS2 and EFR have been identified.[23] Upon ligand recognition, the plant PRRs transduce "PAMP-triggered immunity" (PTI).[24] Plant immune systems also encode resistance proteins that resemble NOD-like receptors (see above), that feature NBS and LRR domains and can also carry other conserved interaction domains such as the TIR cytoplasmic domain found in Toll and Interleukin Receptors.[25] The NBS-LRR proteins are required for effector triggered immunity (ETI).

Secreted PRRs A number of PRRs do not remain associated with the cell that produces them. Complement receptors, collectins, ficolins, pentraxins such as serum amyloid and C-reactive protein, lipid transferases, peptidoglycan recognition proteins (PGRs) and the LRR, XA21D[26] are all secreted proteins. One very important collectin is mannan-binding lectin (MBL), a major PRR of the innate immune system that binds to a wide range of bacteria, viruses, fungi and protozoa. MBL predominantly recognizes certain sugar groups on the surface of microorganisms but also binds phospholipids, nucleic acids and non-glycosylated proteins.[27] Once bound to the ligands MBL and Ficolin oligomers recruit MASP1 and MASP2 and initiate the lectin pathway of complement activation which is somewhat similar to the classical complement pathway.

Signaling via PRR NonRD kinases PRRs commonly associate with or contain members of a monophyletic group of kinases called the interleukin-1 receptor-associated kinase (IRAK) family that include Drosophila Pelle, human IRAKs, rice XA21 and Arabidopsis FLS2. In mammals, PRRs can also associate with members of the receptor-interacting protein (RIP) kinase family, distant relatives to the IRAK family. Some IRAK and RIP family kinases fall into a small functional class of kinases termed non-RD, many of which do not autophosphorylate the activation loop. A survey of the yeast, fly, worm, human, Arabidopsis, and rice kinomes (3,723 kinases) revealed that despite the small number of non-RD kinases in these genomes (9%–29%), 12 of 15 kinases known or predicted to function in PRR signaling fall into the non-RD class.[28] In plants, all PRRs characterized to date belong to the non-RD class. These data indicate that kinases associated with PRRs can largely be predicted by the lack of a single conserved residue and reveal new potential plant PRR subfamilies.

References Mahla, R.S. (2013). "Sweeten PAMPs: Role of Sugar Complexed PAMPs in Innate Immunity and Vaccine Biology". Front Immunol. 4: 248.  Freely accessible. . . Song WY, Wang GL, Chen LL, Kim HS, Pi LY, Holsten T, Gardner J, Wang B, Zhai WX, Zhu LH, Fauquet C, Ronald P (December 1995). "A receptor kinase-like protein encoded by the rice disease resistance gene, Xa21". Science. 270 (5243): 1804–6. . . . Beutler B, Jiang Z, Georgel P, Crozat K, Croker B, Rutschmann S, Du X, Hoebe K (2006). "Genetic analysis of host resistance: Toll-like receptor signaling and immunity at large". Annu. Rev. Immunol. 24: 353–389. . . Doyle SL, O'Neill LA (October 2006). "Toll-like receptors: from the discovery of NFkappaB to new insights into transcriptional regulations in innate immunity". Biochem. Pharmacol. 72 (9): 1102–1113. . . Nat Rev Immunol. 2009 Jul;9(7):465-79. Signalling through C-type lectin receptors: shaping immune responses. Geijtenbeek TB, Gringhuis SI. http://www.mh-hannover.de/fileadmin/mhh/bilder/international/hbrs_mdphd/ZIB/Vorlesungen/Paper_09-10/Rev_IM_Geijtenbeek.pdf Cummings RD, McEver RP. C-type Lectins. In: Varki A, Cummings RD, Esko JD, et al., editors. Essentials of Glycobiology. 2nd edition. Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press; 2009. http://www.ncbi.nlm.nih.gov/books/NBK1943/ Apostolopoulos V, McKenzie IF (September 2001). "Role of the mannose receptor in the immune response". Curr. Mol. Med. 1 (4): 469–74. . . Ting JP, Williams KL (April 2005). "The CATERPILLER family: an ancient family of immune/apoptotic proteins". Clin. Immunol. 115 (1): 33–37. . . Jones DG, Dangl JL (2006). "The plant immune system". Nature. 444 (7117): 323–329. . . . Inohara, Inohara, McDonald C, Nuñez G (2005). "NOD-LRR proteins: role in host-microbial interactions and inflammatory disease". Annu. Rev. Biochem. 74: 355–383. . . Strober W, Murray PJ, Kitani A, Watanabe T (January 2006). "Signalling pathways and molecular interactions of NOD1 and NOD2". Nat. Rev. Immunol. 6 (1): 9–20. . . Bahar O, Pruitt R, Luu DD, Schwessinger B, Daudi A, Liu F, Ruan R, Fontaine-Bodin L, Koebnik R, Ronald P (2014). "The Xanthomonas Ax21 protein is processed by the general secretory system and is secreted in association with outer membrane vesicles". PeerJ. 2: e242. Freely accessible. . . Boller T, Felix G (2009). "A renaissance of elicitors: perception of microbe-associated molecular patterns and danger signals by pattern-recognition receptors". Annu Rev Plant Biol. 60: 379–406. . . Chisholm ST, Coaker G, Day B, Staskawicz BJ (2006). "Host-microbe interactions: shaping the evolution of the plant immune response". Cell. 124 (4): 803–814. . . McHale L, Tan X, Koehl P, Michelmore RW (2006). "Plant NBS-LRR proteins: adaptable guards". Genome Biol. 7 (4): 212.  Freely accessible. . . Wang GL, Ruan DL, Song WY, Sideris S, Chen L, Pi LY, Zhang S, Zhang Z, Fauquet C, Gaut BS, Whalen MC, Ronald PC (May 1998). "Xa21D encodes a receptor-like molecule with a leucine-rich repeat domain that determines race-specific recognition and is subject to adaptive evolution". Plant Cell. 10 (5): 765–79.  Freely accessible. . . Dommett RM, Klein N, Turner MW (September 2006). "Mannose-binding lectin in innate immunity: past, present and future". Tissue Antigens. 68 (3): 193–209. . . Dardick C, Ronald P (January 2006). "Plant and animal pathogen recognition receptors signal through non-RD kinases". PLoS Pathog. 2 (1): e2. Freely accessible. . . External links Pattern Recognition Receptors at the US National Library of Medicine Medical Subject Headings (MeSH) vte Innate immune system: Pattern recognition receptors Membrane-bound_PRRs Toll-like receptor Mannose receptor Formyl peptide receptor Scavenger receptor Cytoplasmic_PRRs Toll-like receptor NOD-like receptor RIG-I-like receptor Scavenger receptor Secreted_PRRs Complement receptor Collectin Other/ungrouped Immunophilins (Cyclophilin) Insert paragraph ↑ Mahla, R.S. (2013). "Sweeten PAMPs: Role of Sugar Complexed PAMPs in Innate Immunity and Vaccine Biology". Front Immunol. 4: 248.  . . . 1 2 Song WY, Wang GL, Chen LL, Kim HS, Pi LY, Holsten T, Gardner J, Wang B, Zhai WX, Zhu LH, Fauquet C, Ronald P (December 1995). "A receptor kinase-like protein encoded by the rice disease resistance gene, Xa21". Science. 270 (5243): 1804–6. . . . ↑ Beutler B, Jiang Z, Georgel P, Crozat K, Croker B, Rutschmann S, Du X, Hoebe K (2006). "Genetic analysis of host resistance: Toll-like receptor signaling and immunity at large". Annu. Rev. Immunol. 24: 353–389. . . ↑ Doyle SL, O'Neill LA (October 2006). "Toll-like receptors: from the discovery of NFkappaB to new insights into transcriptional regulations in innate immunity". Biochem. Pharmacol. 72 (9): 1102–1113. . . ↑ Nat Rev Immunol. 2009 Jul;9(7):465-79. Signalling through C-type lectin receptors: shaping immune responses. Geijtenbeek TB, Gringhuis SI. http://www.mh-hannover.de/fileadmin/mhh/bilder/international/hbrs_mdphd/ZIB/Vorlesungen/Paper_09-10/Rev_IM_Geijtenbeek.pdf↑ Cummings RD, McEver RP. C-type Lectins. In: Varki A, Cummings RD, Esko JD, et al., editors. Essentials of Glycobiology. 2nd edition. Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press; 2009. http://www.ncbi.nlm.nih.gov/books/NBK1943/↑ Apostolopoulos V, McKenzie IF (September 2001). "Role of the mannose receptor in the immune response". Curr. Mol. Med. 1 (4): 469–74. . . 1 2 Ting JP, Williams KL (April 2005). "The CATERPILLER family: an ancient family of immune/apoptotic proteins". Clin. Immunol. 115 (1): 33–37. . . ↑ Jones DG, Dangl JL (2006). "The plant immune system". Nature. 444 (7117): 323–329. . . . ↑ Inohara, Inohara, McDonald C, Nuñez G (2005). "NOD-LRR proteins: role in host-microbial interactions and inflammatory disease". Annu. Rev. Biochem. 74: 355–383. . . CS1 maint: Multiple names: authors list (link)↑ Strober W, Murray PJ, Kitani A, Watanabe T (January 2006). "Signalling pathways and molecular interactions of NOD1 and NOD2". Nat. Rev. Immunol. 6 (1): 9–20. . . ↑ Bahar O, Pruitt R, Luu DD, Schwessinger B, Daudi A, Liu F, Ruan R, Fontaine-Bodin L, Koebnik R, Ronald P (2014). "The Xanthomonas Ax21 protein is processed by the general secretory system and is secreted in association with outer membrane vesicles". PeerJ. 2: e242. . . . 1 2 Boller T, Felix G (2009). "A renaissance of elicitors: perception of microbe-associated molecular patterns and danger signals by pattern-recognition receptors". Annu Rev Plant Biol. 60: 379–406. . . ↑ Chisholm ST, Coaker G, Day B, Staskawicz BJ (2006). "Host-microbe interactions: shaping the evolution of the plant immune response". Cell. 124 (4): 803–814. . . ↑ McHale L, Tan X, Koehl P, Michelmore RW (2006). "Plant NBS-LRR proteins: adaptable guards". Genome Biol. 7 (4): 212.  . . . ↑ Wang GL, Ruan DL, Song WY, Sideris S, Chen L, Pi LY, Zhang S, Zhang Z, Fauquet C, Gaut BS, Whalen MC, Ronald PC (May 1998). "Xa21D encodes a receptor-like molecule with a leucine-rich repeat domain that determines race-specific recognition and is subject to adaptive evolution". Plant Cell. 10 (5): 765–79.  . . . ↑ Dommett RM, Klein N, Turner MW (September 2006). "Mannose-binding lectin in innate immunity: past, present and future". Tissue Antigens. 68 (3): 193–209. . . ↑ Dardick C, Ronald P (January 2006). "Plant and animal pathogen recognition receptors signal through non-RD kinases". PLoS Pathog. 2 (1): e2. . . . Navigation menu Hadlova Petra Alert (1) Notices (2) TalkSandboxPreferencesBetaWatchlistContributionsLog outArticleTalkReadEdit this pageView historySearch

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