Pattern Recognition Receptors

Abstract

Multicellular organisms continually come into contact with microbes in the environment, and protecting themselves from infection is vital to their survival. The innate immune system has a critically important role in acting as a first line of defence against this threat, by rapidly detecting and destroying any foreign invaders. Recognition of pathogens by the innate immune system is achieved through the actions of a large collection of pattern recognition receptors that bind to unique features of pathogens called pathogen‐associated molecular patterns that are not normally found in the host. Recognition is followed by the production of cytokines and chemokines and activation of innate immune responses that restrict, destroy and dispose of the pathogen and promote the subsequent activation of an adaptive immune response.

Key Concepts

  • Pattern recognition receptors (PRRs) detect foreign molecules associated with pathogens, termed pathogen‐associated molecular patterns (PAMPs).
  • PAMPs are specific to groups of pathogens and are not normally found in the host.
  • PRRs are found in different tissues and in different subcellular compartments according to the types of pathogen that they recognise.
  • Activation of PRRs leads to innate immune responses that destroy the pathogen.

Keywords: innate immunity; pattern recognition receptor; pathogen‐associated molecular pattern; cytokines; inflammasome

Figure 1. Toll‐like receptors (TLRs). TLRs exist as homo‐ or hetero‐dimeric transmembrane proteins located on the plasma membrane (PM) or on the endosome. The leucine‐rich repeat (LRR) domain faces the extracellular space or lumen of the endosome and is responsible for ligand binding. The cytoplasmic tail contains the Toll/interleukin‐1 receptor (TIR) domain that interacts with adaptor proteins that mediate signal transduction.
Figure 2. Intracellular nucleic acid receptors. The RLRs contain a DExD/H box RNA helicase domain responsible for binding dsRNA ligands and two ‐terminal caspase activation and recruitment domains (CARDs) that interact with the adaptor protein MAVS to activate downstream signalling. The DNA sensor cyclic GMP‐AMP (GAMP) synthase (cGAS) generates cGAMP from ATP and GTP, which activates stimulator of interferon genes (STING). Foreign DNA in the nucleus is detected by the pyhin protein IFI16 that has two HIN domains that bind DNA and a single ‐terminal pyrin domain (PYD). Activated IFI16 translocates into the cytoplasm to activate both STING and the inflammasome. AIM2 contains a ‐terminal HIN domain and an ‐terminal PYD that interacts with ASC to form the inflammasome.
Figure 3. Nucleotide‐binding leucine‐rich repeat containing receptors (NLRs). The NLRs contain a central nucleotide‐binding and oligomerisation domain (NOD) and ‐terminal leucine‐rich repeats (LRRs) that are responsible for ligand binding. The NLRs are grouped into subfamilies based on the composition of their ‐terminal domains. NAIP contains three baculovirus inhibitor of apoptosis protein repeat (BIR) domains. The NLRC subfamily contains one or two CARDs, and the NLRP subfamily has a pyrin domain (PYD) at the ‐terminus. These ‐terminal domains transmit signals to downstream adaptors.
Figure 4. C‐type lectin receptors and scavenger receptors. The C‐type lectin receptors are single‐pass transmembrane proteins characterised by the presence of one or more extracellular C‐type lectin‐like domains (CTLDs) that bind various carbohydrate and non‐carbohydrate ligands. Dectin‐1 has an immunoreceptor tyrosine‐based activation motif (ITAM) on its cytoplasmic tail that interacts with Syk, whereas Dectin‐2 and Mincle lack their own ITAM motif and instead interact with the ITAM‐containing FcRγ. DC‐SIGN has a single CTLD and exists as a tetramer, whereas the mannose receptor has a more extensive extracellular domain containing eight CTLDs. The scavenger receptors SR‐A1 and SR‐A6 (MARCO) exist as homotrimers with a single transmembrane domain, an α‐helical coiled‐coil domain (α) (SR‐A1 only), a collagenous domain (CD) and a cysteine‐rich domain (C). SR‐B2 has two transmembrane domains with an extracellular ligand‐binding loop and intracellular ‐ and ‐terminal tails.
close

References

Abe T, Harashima A, Xia T, et al. (2013) STING recognition of cytoplasmic DNA instigates cellular defense. Molecular Cell 50 (1): 5–15.

Abe T and Barber GN (2014) Cytosolic‐DNA‐mediated, STING‐dependent proinflammatory gene induction necessitates canonical NF‐κB activation through TBK1. Journal of Virology 88 (10): 5328–5341.

Ansari MA, Dutta S, Veettil MV, et al. (2015) Herpesvirus genome recognition induced acetylation of nuclear IFI16 is essential for its cytoplasmic translocation, inflammasome and IFN‐β responses. PLoS Pathogens 11 (7): e1005019.

Arredouani M, Yang Z, Ning Y, et al. (2004) The scavenger receptor MARCO is required for lung defense against pneumococcal pneumonia and inhaled particles. The Journal of Experimental Medicine 200 (2): 267–272.

Bürckstümmer T, Baumann C, Blüml S, et al. (2009) An orthogonal proteomic‐genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome. Nature Immunology 10 (3): 266–272.

Burdette DL, Monroe KM, Sotelo‐Troha K, et al. (2011) STING is a direct innate immune sensor of cyclic di‐GMP. Nature 478 (7370): 515–518.

Diner BA, Li T, Greco TM, et al. (2015) The functional interactome of PYHIN immune regulators reveals IFIX is a sensor of viral DNA. Molecular Systems Biology 11 (2): 787.

Fernandes‐Alnemri T, Yu J‐W, Datta P, et al. (2009) AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature 458 (7237): 509–513.

Gitlin L, Barchet W, Gilfillan S, et al. (2006) Essential role of mda‐5 in type I IFN responses to polyriboinosinic:polyribocytidylic acid and encephalomyocarditis picornavirus. Proceedings of the National Academy of Sciences of the United States of America 103 (22): 8459–8464.

Gringhuis SI, den Dunnen J, Litjens M, et al. (2007) C‐type lectin DC‐SIGN modulates Toll‐like receptor signaling via Raf‐1 kinase‐dependent acetylation of transcription factor NF‐kappaB. Immunity 26 (5): 605–616.

Gringhuis SI, den Dunnen J, Litjens M, et al. (2009) Dectin‐1 directs T helper cell differentiation by controlling noncanonical NF‐kappaB activation through Raf‐1 and Syk. Nature Immunology 10 (2): 203–213.

Gringhuis SI, Kaptein TM, Wevers BA, et al. (2012) Dectin‐1 is an extracellular pathogen sensor for the induction and processing of IL‐1β via a noncanonical caspase‐8 inflammasome. Nature Immunology 13 (3): 246–254.

Gross O, Poeck H, Bscheider M, et al. (2009) Syk kinase signalling couples to the Nlrp3 inflammasome for anti‐fungal host defence. Nature 459 (7245): 433–436.

Hemmi H, Kaisho T, Takeuchi O, et al. (2002) Small anti‐viral compounds activate immune cells via the TLR7 MyD88–dependent signaling pathway. Nature Immunology 3 (2): 196–200.

Holm CK, Jensen SB, Jakobsen MR, et al. (2012) Virus‐cell fusion as a trigger of innate immunity dependent on the adaptor STING. Nature Immunology 13 (8): 737–743.

Hornung V, Ablasser A, Charrel‐Dennis M, et al. (2009) AIM2 recognizes cytosolic dsDNA and forms a caspase‐1‐activating inflammasome with ASC. Nature 458 (7237): 514–518.

Ishikawa H, Ma Z and Barber GN (2009) STING regulates intracellular DNA‐mediated, type I interferon‐dependent innate immunity. Nature 461 (7265): 788–792.

Kato H, Takeuchi O, Sato S, et al. (2006) Differential roles of MDA5 and RIG‐I helicases in the recognition of RNA viruses. Nature 441 (7089): 101–105.

Kerur N, Veettil MV, Sharma‐Walia N, et al. (2011) IFI16 acts as a nuclear pathogen sensor to induce the inflammasome in response to kaposi sarcoma‐associated herpesvirus infection. Cell Host & Microbe 9 (5): 363–375.

Lee SMY, Kok K‐H, Jaume M, et al. (2014) Toll‐like receptor 10 is involved in induction of innate immune responses to influenza virus infection. Proceedings of the National Academy of Sciences of the United States of America 111 (10): 3793–3798.

Loo YM, Fornek J, Crochet N, et al. (2008) Distinct RIG‐I and MDA5 signaling by RNA viruses in innate immunity. Journal of Virology 82 (1): 335–345.

Mankan AK, Schmidt T, Chauhan D, et al. (2014) Cytosolic RNA:DNA hybrids activate the cGAS‐STING axis. The EMBO Journal 33 (24): 2937–2946.

Oosting M, Cheng S‐C, Bolscher JM, et al. (2014) Human TLR10 is an anti‐inflammatory pattern‐recognition receptor. Proceedings of the National Academy of Sciences of the United States of America 111 (42): E4478–E4484.

Peisley A, Lin C, Wu B, et al. (2011) Cooperative assembly and dynamic disassembly of MDA5 filaments for viral dsRNA recognition. Proceedings of the National Academy of Sciences of the United States of America 108 (52): 21010–21015.

Prabhudas M, Bowdish D, Drickamer K, et al. (2014) Standardizing scavenger receptor nomenclature. Journal of Immunology 192 (5): 1997–2006.

Regan T, Nally K, Carmody R, et al. (2013) Identification of TLR10 as a key mediator of the inflammatory response to listeria monocytogenes in intestinal epithelial cells and macrophages. The Journal of Immunology 191 (12): 6084–6092.

Sidiq T, Yoshihama S, Downs I, et al. (2016) Nod2: a critical regulator of ileal microbiota and Crohn's disease. Frontiers in Immunology 7: 367.

Sun L, Wu J, Du F, et al. (2013) Cyclic GMP‐AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science 339 (6121): 786–791.

Tanaka Y and Chen ZJ (2012) STING specifies IRF3 phosphorylation by TBK1 in the cytosolic DNA signaling pathway. Science Signaling 5 (214): ra20.

Tanji H, Ohto U, Shibata T, et al. (2015) Toll‐like receptor 8 senses degradation products of single‐stranded RNA. Nature Structural & Molecular Biology 22 (2): 109–115.

Travassos LH, Carneiro LAM, Ramjeet M, et al. (2010) Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry. Nature Immunology 11 (1): 55–62.

Unterholzner L, Keating SE, Baran M, et al. (2010) IFI16 is an innate immune sensor for intracellular DNA. Nature Immunology 11 (11): 997–1004.

Venkataraman T, Valdes M, Elsby R, et al. (2007) Loss of DExD/H box RNA helicase LGP2 manifests disparate antiviral responses. Journal of Immunology 178 (10): 6444–6455.

Yadav M and Schorey JS (2006) The beta‐glucan receptor dectin‐1 functions together with TLR2 to mediate macrophage activation by mycobacteria. Blood 108 (9): 3168–3175.

Zhang Z, Ohto U, Shibata T, et al. (2016) Structural analysis reveals that toll‐like receptor 7 is a dual receptor for guanosine and single‐stranded RNA. Immunity 45 (4): 737–748.

Further Reading

Barbé F, Douglas T and Saleh M (2014) Advances in nod‐like receptors (NLR) biology. Cytokine and Growth Factor Reviews 25: 681–697.

Brubaker SW, Bonham KS, Zanoni I, et al. (2015) Innate immune pattern recognition: a cell biological perspective. Annual Reviews in Immunology 33: 257–290.

Canton J, Neculai D and Grinstein S (2013) Scavenger receptors in homeostasis and immunity. Nature Reviews Immunology 13: 621–634.

Chuenchor W, Jin T, Ravilious G, et al. (2014) Structures of pattern recognition receptors reveal molecular mechanisms of autoinhibition, ligand recognition and oligomerisation. Current Opinion in Immunology 26: 14–20.

Dempsey A and Bowie AG (2015) Innate immune recognition of DNA: a recent history. Virology 479‐480: 146–152.

Hoving JC, Wilson GJ and Brown GD (2014) Signalling C‐Type lectin receptors, microbial recognition and immunity. Cellular Microbiology 16: 185–194.

Kawai T and Akira S (2010) The role of pattern‐recognition receptors in innate immunity: update on toll‐like receptors. Nature Immunology 11: 373–384.

Philpott DJ, Sorbara MT, Robertson SJ, et al. (2014) NOD proteins: regulators of inflammation in health and disease. Nature Reviews Immunology 14: 9–23.

Sancho D and Reis e Sousa C (2012) Signaling by myeloid C‐type lectin receptors in immunity and homeostasis. Annual Reviews in Immunology 30: 491–529.

Yoneyama M, Onomoto K, Jogi M, et al. (2015) Viral RNA detection by RIG‐I‐like receptors. Current Opinion in Immunology 32: 48–53.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Childs, KS, and Goodbourn, S(May 2017) Pattern Recognition Receptors. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0020175.pub2]