Peptidoglycan recognition protein 3 explained

Peptidoglycan recognition protein 3 (PGLYRP3, formerly PGRP-Iα) is an antibacterial and anti-inflammatory innate immunity protein that in humans is encoded by the PGLYRP3 gene.[1] [2] [3]

Discovery

PGLYRP3 (formerly PGRP-Iα), a member of a family of human Peptidoglycan Recognition Proteins (PGRPs), was discovered in 2001 by Roman Dziarski and coworkers who cloned and identified the genes for three human PGRPs, PGRP-L, PGRP-Iα, and PGRP-Iβ (named for long and intermediate size transcripts), and established that human genome codes for a family of 4 PGRPs: PGRP-S (short PGRP or PGRP-S)[4] and PGRP-L, PGRP-Iα, and PGRP-Iβ. Subsequently, the Human Genome Organization Gene Nomenclature Committee changed the gene symbols of PGRP-S, PGRP-L, PGRP-Iα, and PGRP-Iβ to PGLYRP1 (peptidoglycan recognition protein 1), PGLYRP2 (peptidoglycan recognition protein 2), PGLYRP3 (peptidoglycan recognition protein 3), and PGLYRP4 (peptidoglycan recognition protein 4), respectively, and this nomenclature is currently also used for other mammalian PGRPs.

Tissue distribution and secretion

PGLYRP3 has similar expression to PGLYRP4 (peptidoglycan recognition protein 4) but not identical.[5] PGLYRP3 is constitutively expressed in the skin, in the eye, and in the mucous membranes in the tongue, throat, and esophagus, and at a much lower level in the remaining parts of the intestinal tract.[6] [7] Bacteria and their products increase the expression of PGLYRP3 in keratinocytes and oral epithelial cells.[8] Mouse PGLYRP3 is also differentially expressed in the developing brain and this expression is influenced by the intestinal microbiome.[9] PGLYRP3 is secreted and forms disulfide-linked dimers.

Structure

PGLYRP3, similar to PGLYRP4, has two peptidoglycan-binding type 2 amidase domains (also known as PGRP domains), which are not identical (have 38% amino acid identity in humans)[10] and do not have amidase enzymatic activity.[11] PGLYRP3 is secreted, it is glycosylated, and its glycosylation is required for its bactericidal activity. PGLYRP3 forms disulfide-linked homodimers, but when expressed in the same cells with PGLYRP4, it forms PGLYRP3:PGLYRP4 disulfide-linked heterodimers.

The C-terminal peptidoglycan-binding domain of human PGLYRP3 has been crystallized and its structure solved[12] and is similar to human PGLYRP1.[13] PGLYRP3 C-terminal PGRP domain contains a central β-sheet composed of five β-strands and three α-helices and N-terminal segment unique to PGRPs and not found in bacteriophage and prokaryotic amidases.

Human PGLYRP3 C-terminal PGRP domain, similar to PGLYRP1, has three pairs of cysteines, which form three disulfide bonds at positions 178–300, 194–238, and 214–220. The Cys214–Cys220 disulfide is broadly conserved in invertebrate and vertebrate PRGPs, the Cys178–Cys300 disulfide is conserved in all mammalian PGRPs, and the Cys194–238 disulfide is unique to mammalian PGLYRP1, PGLYRP3, and PGLYRP4, but not found in the amidase-active PGLYRP2. The structures of the entire PGLYRP3 molecule (with two PGRP domains) and of the disulfide-linked dimer are unknown.

PGLYRP3 C-terminal PGRP domain contains peptidoglycan-binding site, which is a long cleft whose walls are formed by α-helix and five β-loops and the floor by a β-sheet. This site binds muramyl-tripeptide (MurNAc-L-Ala-D-isoGln-L-Lys), but can also accommodate larger peptidoglycan fragments, such as disaccharide-pentapeptide.[14] Located opposite the peptidoglycan-binding cleft is a large hydrophobic groove, formed by residues 177–198 (the PGRP-specific segment).

Functions

The PGLYRP3 protein plays an important role in the innate immune responses.

Peptidoglycan binding

PGLYRP3 binds peptidoglycan, a polymer of β(1-4)-linked N-acetylglucosamine (GlcNAc) and N-acetylmuramic acid (MurNAc) cross-linked by short peptides, the main component of bacterial cell wall.[15] [16] The smallest peptidoglycan fragment that binds to human PGLYRP3 is MurNAc-tripeptide (MurNAc-L-Ala-D-isoGln-L-Lys), which binds with low affinity (Kd = 4.5 x 10−4 M), whereas a larger fragment, MurNAc-pentapeptide (MurNAc-L-Ala-γ-D-Gln-L-Lys-D-Ala-D-Ala), binds with higher affinity (Kd = 6 x 10-6  M).[17] Human PGLYRP3, in contrast to PGLYRP1, does not bind meso-diaminopimelic acid (m-DAP) containing fragment (MurNAc-L-Ala-γ-D-Gln-DAP-D-Ala-D-Ala). m-DAP is present in the third position of peptidoglycan peptide in Gram-negative bacteria and Gram-positive bacilli, whereas L-lysine is in this position in peptidoglycan peptide in Gram-positive cocci. Thus, PGLYRP3 C-terminal PGRP domain has a preference for binding peptidoglycan fragments from Gram-positive cocci. Binding of MurNAc-pentapeptide induces structural rearrangements in the binding site that are essential for entry of the ligand and locks the ligand in the binding cleft.[18] The fine specificity of the PGLYRP3 N-terminal PGRP domain is not known.

Bactericidal activity

Human PGLYRP3 is directly bactericidal for both Gram-positive (Bacillus subtilis, Bacillus licheniformis, Bacillus cereus, Lactobacillus acidophilus, Listeria monocytogenes, Staphylococcus aureus, Streptococcus pyogenes) and Gram-negative (Escherichia coli, Proteus vulgaris, Salmonella enterica, Shigella sonnei, Pseudomonas aeruginosa) bacteria.[19] [20] [21]

The mechanism of bacterial killing by PGLYRP3 is based on induction of lethal envelope stress, which eventually leads to the shutdown of transcription and translation. PGLYRP3-induced killing involves simultaneous induction of three stress responses in both Gram-positive and Gram-negative bacteria: oxidative stress due to production of reactive oxygen species (hydrogen peroxide and hydroxyl radicals), thiol stress due to depletion (oxidation) of cellular thiols, and metal stress due to an increase in intracellular free (labile) metal ions. PGLYRP3-induced bacterial killing does not involve cell membrane permeabilization, which is typical for defensins and other antimicrobial peptides, cell wall hydrolysis, or osmotic shock. Human PGLYRP3 has synergistic bactericidal activity with antibacterial peptides.

Defense against infections

PGLYRP3 plays a limited role in host defense against infections. Intranasal administration of PGLYRP3 protects mice from lung infection with S. aureus and E. coli,[22] but PGLYRP3-deficient mice do not have altered sensitivity to Streptococcus pneumoniae-induced pneumonia.[23]

Maintaining microbiome

Mouse PGLYRP3 plays a role in maintaining healthy microbiome, as PGLYRP3-deficient mice have significant changes in the composition of their intestinal microbiome, which affect their sensitivity to colitis.[24] [25]

Effects on inflammation

Mouse PGLYRP3 plays a role in maintaining anti- and pro-inflammatory homeostasis in the intestine and skin. PGLYRP3-deficient mice are more sensitive than wild type mice to dextran sodium sulfate (DSS)-induced colitis, which indicates that PGLYRP3 protects mice from DSS-induced colitis. The anti-inflammatory effect of PGLYRP3 on DSS-induced colitis depends on the PGLYRP3-regulated intestinal microbiome, because this greater sensitivity of PGLYRP3-deficient mice to DSS-induced colitis could be transferred to wild type germ-free mice or to antibiotic-treated mice by microbiome transplant from PGLYRP3-deficient mice or by PGLYRP3-regulated bacteria. PGLYRP3 is also directly anti-inflammatory in intestinal epithelial cells.[26] [27] [28]

PGLYRP3-deficient mice are more sensitive than wild type mice to experimentally induced atopic dermatitis.[29] These results indicate that mouse PGLYRP3 is anti-inflammatory and protects skin from inflammation. This anti-inflammatory effect is due to decreased numbers and activity of T helper 17 (Th17) cells and increased numbers of T regulatory (Treg) cells.

Medical relevance

Genetic PGLYRP3 variants are associated with some diseases. Patients with inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis, have significantly more frequent missense variants in PGLYRP3 gene (and also in the other three PGLYRP genes) than healthy controls. PGLYRP3 variants are also associated with Parkinson's disease[30] and psoriasis.[31] [32] These results suggest that PGLYRP3 protects humans from these diseases, and that mutations in PGLYRP3 gene are among the genetic factors predisposing to these diseases. PGLYRP3 variants are also associated with the composition of airway microbiome.[33]

See also

Further reading

Notes and References

  1. Liu C, Xu Z, Gupta D, Dziarski R . Peptidoglycan recognition proteins: a novel family of four human innate immunity pattern recognition molecules . The Journal of Biological Chemistry . 276 . 37 . 34686–94 . September 2001 . 11461926 . 10.1074/jbc.M105566200 . 44619852 . free .
  2. Web site: PGLYRP3 peptidoglycan recognition protein 3 [Homo sapiens (human)] - Gene - NCBI]. 2020-11-02. www.ncbi.nlm.nih.gov.
  3. Web site: PGLYRP3 - Peptidoglycan recognition protein 3 precursor - Homo sapiens (Human) - PGLYRP3 gene & protein. 2020-11-02. www.uniprot.org. en.
  4. Kang D, Liu G, Lundström A, Gelius E, Steiner H . A peptidoglycan recognition protein in innate immunity conserved from insects to humans . Proceedings of the National Academy of Sciences of the United States of America . 95 . 17 . 10078–82 . August 1998 . 9707603 . 21464 . 10.1073/pnas.95.17.10078 . 1998PNAS...9510078K . free .
  5. Lu X, Wang M, Qi J, Wang H, Li X, Gupta D, Dziarski R . Peptidoglycan recognition proteins are a new class of human bactericidal proteins . The Journal of Biological Chemistry . 281 . 9 . 5895–907 . March 2006 . 16354652 . 10.1074/jbc.M511631200 . 21943426 . free .
  6. Mathur P, Murray B, Crowell T, Gardner H, Allaire N, Hsu YM, Thill G, Carulli JP . 6 . Murine peptidoglycan recognition proteins PglyrpIalpha and PglyrpIbeta are encoded in the epidermal differentiation complex and are expressed in epidermal and hematopoietic tissues . Genomics . 83 . 6 . 1151–63 . June 2004 . 15177568 . 10.1016/j.ygeno.2004.01.003 .
  7. Saha S, Jing X, Park SY, Wang S, Li X, Gupta D, Dziarski R . Peptidoglycan recognition proteins protect mice from experimental colitis by promoting normal gut flora and preventing induction of interferon-gamma . Cell Host & Microbe . 8 . 2 . 147–62 . August 2010 . 20709292 . 2998413 . 10.1016/j.chom.2010.07.005 .
  8. Uehara A, Sugawara Y, Kurata S, Fujimoto Y, Fukase K, Kusumoto S, Satta Y, Sasano T, Sugawara S, Takada H . 6 . Chemically synthesized pathogen-associated molecular patterns increase the expression of peptidoglycan recognition proteins via toll-like receptors, NOD1 and NOD2 in human oral epithelial cells . Cellular Microbiology . 7 . 5 . 675–86 . May 2005 . 15839897 . 10.1111/j.1462-5822.2004.00500.x . 20544993 . free .
  9. Arentsen T, Qian Y, Gkotzis S, Femenia T, Wang T, Udekwu K, Forssberg H, Diaz Heijtz R . 6 . The bacterial peptidoglycan-sensing molecule Pglyrp2 modulates brain development and behavior . Molecular Psychiatry . 22 . 2 . 257–266 . February 2017 . 27843150 . 5285465 . 10.1038/mp.2016.182 .
  10. Zulfiqar F, Hozo I, Rangarajan S, Mariuzza RA, Dziarski R, Gupta D . Genetic Association of Peptidoglycan Recognition Protein Variants with Inflammatory Bowel Disease . PLOS ONE . 8 . 6 . e67393 . 2013 . 23840689 . 3686734 . 10.1371/journal.pone.0067393 . 2013PLoSO...867393Z . free .
  11. Wang ZM, Li X, Cocklin RR, Wang M, Wang M, Fukase K, Inamura S, Kusumoto S, Gupta D, Dziarski R . 6 . Human peptidoglycan recognition protein-L is an N-acetylmuramoyl-L-alanine amidase . The Journal of Biological Chemistry . 278 . 49 . 49044–52 . December 2003 . 14506276 . 10.1074/jbc.M307758200 . 35373818 . free .
  12. Guan R, Malchiodi EL, Wang Q, Schuck P, Mariuzza RA . Crystal structure of the C-terminal peptidoglycan-binding domain of human peptidoglycan recognition protein Ialpha . The Journal of Biological Chemistry . 279 . 30 . 31873–82 . July 2004 . 15140887 . 10.1074/jbc.M404920200 . 29969809 . free .
  13. Guan R, Wang Q, Sundberg EJ, Mariuzza RA . Crystal structure of human peptidoglycan recognition protein S (PGRP-S) at 1.70 A resolution . Journal of Molecular Biology . 347 . 4 . 683–91 . April 2005 . 15769462 . 10.1016/j.jmb.2005.01.070 .
  14. Guan R, Roychowdhury A, Ember B, Kumar S, Boons GJ, Mariuzza RA . Structural basis for peptidoglycan binding by peptidoglycan recognition proteins . Proceedings of the National Academy of Sciences of the United States of America . 101 . 49 . 17168–73 . December 2004 . 15572450 . 535381 . 10.1073/pnas.0407856101 . 2004PNAS..10117168G . free .
  15. Kumar S, Roychowdhury A, Ember B, Wang Q, Guan R, Mariuzza RA, Boons GJ . Selective recognition of synthetic lysine and meso-diaminopimelic acid-type peptidoglycan fragments by human peptidoglycan recognition proteins I and S . The Journal of Biological Chemistry . 280 . 44 . 37005–12 . November 2005 . 16129677 . 10.1074/jbc.M506385200 . 44913130 . free .
  16. Swaminathan CP, Brown PH, Roychowdhury A, Wang Q, Guan R, Silverman N, Goldman WE, Boons GJ, Mariuzza RA . 6 . Dual strategies for peptidoglycan discrimination by peptidoglycan recognition proteins (PGRPs) . Proceedings of the National Academy of Sciences of the United States of America . 103 . 3 . 684–9 . January 2006 . 16407132 . 1334652 . 10.1073/pnas.0507656103 . 2006PNAS..103..684S . free .
  17. Cho S, Wang Q, Swaminathan CP, Hesek D, Lee M, Boons GJ, Mobashery S, Mariuzza RA . 6 . Structural insights into the bactericidal mechanism of human peptidoglycan recognition proteins . Proceedings of the National Academy of Sciences of the United States of America . 104 . 21 . 8761–6 . May 2007 . 17502600 . 1885576 . 10.1073/pnas.0701453104 . 2007PNAS..104.8761C . free .
  18. Guan R, Brown PH, Swaminathan CP, Roychowdhury A, Boons GJ, Mariuzza RA . Crystal structure of human peptidoglycan recognition protein I alpha bound to a muramyl pentapeptide from Gram-positive bacteria . Protein Science . 15 . 5 . 1199–206 . May 2006 . 16641493 . 2242522 . 10.1110/ps.062077606 .
  19. Wang M, Liu LH, Wang S, Li X, Lu X, Gupta D, Dziarski R . Human peptidoglycan recognition proteins require zinc to kill both gram-positive and gram-negative bacteria and are synergistic with antibacterial peptides . Journal of Immunology . 178 . 5 . 3116–25 . March 2007 . 17312159 . 10.4049/jimmunol.178.5.3116 . 22160694 . free .
  20. Kashyap DR, Wang M, Liu LH, Boons GJ, Gupta D, Dziarski R . Peptidoglycan recognition proteins kill bacteria by activating protein-sensing two-component systems . Nature Medicine . 17 . 6 . 676–83 . June 2011 . 21602801 . 3176504 . 10.1038/nm.2357 .
  21. Kashyap DR, Rompca A, Gaballa A, Helmann JD, Chan J, Chang CJ, Hozo I, Gupta D, Dziarski R . 6 . Peptidoglycan recognition proteins kill bacteria by inducing oxidative, thiol, and metal stress . PLOS Pathogens . 10 . 7 . e1004280 . July 2014 . 25032698 . 4102600 . 10.1371/journal.ppat.1004280 . free .
  22. Dziarski R, Kashyap DR, Gupta D . Mammalian peptidoglycan recognition proteins kill bacteria by activating two-component systems and modulate microbiome and inflammation . Microbial Drug Resistance . 18 . 3 . 280–5 . June 2012 . 22432705 . 3412580 . 10.1089/mdr.2012.0002 .
  23. Shrivastav A, Dabrowski AN, Conrad C, Baal N, Hackstein H, Plog S, Dietert K, Gruber AD, N'Guessan PD, Aly S, Suttorp N, Zahlten J . 6 . Peptidoglycan Recognition Protein 3 Does Not Alter the Outcome of Pneumococcal Pneumonia in Mice . Frontiers in Microbiology . 9 . 103 . 2018 . 29449834 . 5799233 . 10.3389/fmicb.2018.00103 . free .
  24. Dziarski R, Park SY, Kashyap DR, Dowd SE, Gupta D . Pglyrp-Regulated Gut Microflora Prevotella falsenii, Parabacteroides distasonis and Bacteroides eggerthii Enhance and Alistipes finegoldii Attenuates Colitis in Mice . PLOS ONE . 11 . 1 . e0146162 . 2016 . 26727498 . 4699708 . 10.1371/journal.pone.0146162 . 2016PLoSO..1146162D . free .
  25. Jing X, Zulfiqar F, Park SY, Núñez G, Dziarski R, Gupta D . Peptidoglycan recognition protein 3 and Nod2 synergistically protect mice from dextran sodium sulfate-induced colitis . Journal of Immunology . 193 . 6 . 3055–69 . September 2014 . 25114103 . 4157132 . 10.4049/jimmunol.1301548 .
  26. Zenhom M, Hyder A, Kraus-Stojanowic I, Auinger A, Roeder T, Schrezenmeir J . PPARγ-dependent peptidoglycan recognition protein 3 (PGlyRP3) expression regulates proinflammatory cytokines by microbial and dietary fatty acids . Immunobiology . 216 . 6 . 715–24 . June 2011 . 21176858 . 10.1016/j.imbio.2010.10.008 .
  27. Zenhom M, Hyder A, de Vrese M, Heller KJ, Roeder T, Schrezenmeir J . Peptidoglycan recognition protein 3 (PglyRP3) has an anti-inflammatory role in intestinal epithelial cells . Immunobiology . 217 . 4 . 412–9 . April 2012 . 22099350 . 10.1016/j.imbio.2011.10.013 .
  28. Zenhom M, Hyder A, de Vrese M, Heller KJ, Roeder T, Schrezenmeir J . Prebiotic oligosaccharides reduce proinflammatory cytokines in intestinal Caco-2 cells via activation of PPARγ and peptidoglycan recognition protein 3 . The Journal of Nutrition . 141 . 5 . 971–7 . May 2011 . 21451128 . 10.3945/jn.110.136176 . free .
  29. Park SY, Gupta D, Kim CH, Dziarski R . Differential effects of peptidoglycan recognition proteins on experimental atopic and contact dermatitis mediated by Treg and Th17 cells . PLOS ONE . 6 . 9 . e24961 . 2011 . 21949809 . 3174980 . 10.1371/journal.pone.0024961 . 2011PLoSO...624961P . free .
  30. Goldman SM, Kamel F, Ross GW, Jewell SA, Marras C, Hoppin JA, Umbach DM, Bhudhikanok GS, Meng C, Korell M, Comyns K, Hauser RA, Jankovic J, Factor SA, Bressman S, Lyons KE, Sandler DP, Langston JW, Tanner CM . 6 . Peptidoglycan recognition protein genes and risk of Parkinson's disease . Movement Disorders . 29 . 9 . 1171–80 . August 2014 . 24838182 . 4777298 . 10.1002/mds.25895 .
  31. Sun C, Mathur P, Dupuis J, Tizard R, Ticho B, Crowell T, Gardner H, Bowcock AM, Carulli J . 6 . Peptidoglycan recognition proteins Pglyrp3 and Pglyrp4 are encoded from the epidermal differentiation complex and are candidate genes for the Psors4 locus on chromosome 1q21 . Human Genetics . 119 . 1–2 . 113–25 . March 2006 . 16362825 . 10.1007/s00439-005-0115-8 . 31486449 .
  32. Kainu K, Kivinen K, Zucchelli M, Suomela S, Kere J, Inerot A, Baker BS, Powles AV, Fry L, Samuelsson L, Saarialho-Kere U . 6 . Association of psoriasis to PGLYRP and SPRR genes at PSORS4 locus on 1q shows heterogeneity between Finnish, Swedish and Irish families . Experimental Dermatology . 18 . 2 . 109–15 . February 2009 . 18643845 . 10.1111/j.1600-0625.2008.00769.x . 5771478 .
  33. Igartua C, Davenport ER, Gilad Y, Nicolae DL, Pinto J, Ober C . Host genetic variation in mucosal immunity pathways influences the upper airway microbiome . Microbiome . 5 . 1 . 16 . February 2017 . 28143570 . 5286564 . 10.1186/s40168-016-0227-5 . free .

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