Biology:Peptidoglycan recognition protein 4

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File:Human PGLYRP4 gene, cDNA, and protein.tif Peptidoglycan recognition protein 4 (PGLYRP4, formerly PGRP-Iβ) is an antibacterial and anti-inflammatory innate immunity protein that in humans is encoded by the PGLYRP4 gene.[1][2][3][4]

Discovery

PGLYRP4 (formerly PGRP-Iβ), 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),[1] and established that human genome codes for a family of 4 PGRPs: PGRP-S (short PGRP or PGRP-S[5]) and PGRP-L, PGRP-Iα, and PGRP-Iβ.[1] 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

PGLYRP4 has similar expression to PGLYRP3 (peptidoglycan recognition protein 3) but not identical.[1][2] PGLYRP4 is constitutively expressed in the skin, in the eye, in the mucous membranes in the tongue, throat, and esophagus, in the salivary glands and mucus-secreting cells in the throat, and at a much lower level in the remaining parts of the intestinal tract.[1][2][6][7] Bacteria and their products increase the expression of PGLYRP4 in keratinocytes and oral epithelial cells.[2][8] Mouse PGLYRP4 is also differentially expressed in the developing brain and this expression is influenced by the intestinal microbiome.[9] PGLYRP4 is secreted and forms disulfide-linked dimers.[2]

Structure

PGLYRP4, similar to PGLYRP3, has two peptidoglycan-binding type 2 amidase domains (also known as PGRP domains), which are not identical (have 34% amino acid identity in humans)[1][10] and do not have amidase enzymatic activity.[11] PGLYRP4 is secreted, it is glycosylated, and its glycosylation is required for its bactericidal activity.[2] PGLYRP4 forms disulfide-linked homodimers, but when expressed in the same cells with PGLYRP3, it forms PGLYRP3:PGLYRP4 disulfide-linked heterodimers.[2]

The C-terminal peptidoglycan-binding domain of human PGLYRP4 has been crystallized and its structure solved (in a free form and in a complex with peptidoglycan fragment, disaccharide-pentapeptide)[12] and is similar to human PGLYRP1[13] and PGLYRP3.[14][15] PGLYRP4 C-terminal PGRP domain contains central β-sheet composed of six β-strands surrounded by three α-helices and three short helices and N-terminal segment unique to PGRPs and not found in bacteriophage and prokaryotic amidases.[12] PGLYRP4 C-terminal PGRP domain contains three disulfide bonds, one broadly conserved in invertebrate and vertebrate PRGPs, one conserved in all mammalian PGRPs, and one unique to mammalian PGLYRP1, PGLYRP3, and PGLYRP4, but not found in the amidase-active PGLYRP2.[1][11][12][13][14] The structures of the entire PGLYRP4 molecule (with two PGRP domains) and of the disulfide-linked dimer are unknown.

Functions

The PGLYRP4 protein plays an important role in the innate immune responses.

Peptidoglycan binding

PGLYRP4 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.[1][2][12] PGLYRP4 (its C-terminal PGRP domain) binds peptidoglycan fragment, MurNAc-pentapeptide (MurNAc-L-Ala-γ-D-Gln-L-Lys-D-Ala-D-Ala), with Kd = 1.2 x 10−5, but similar to PGLYRP3 (and unlike PGLYRP1) does not bind meso-diaminopimelic acid (m-DAP)-containing fragment (MurNAc-L-Ala-γ-D-Gln-DAP-D-Ala-D-Ala).[12] 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, PGLYRP4 C-terminal PGRP domain has a preference for binding peptidoglycan fragments from Gram-positive cocci. The fine specificity of the PGLYRP4 N-terminal PGRP domain is not known.

Bactericidal activity

Human PGLYRP4 is directly bactericidal for both Gram-positive (Bacillus subtilis, Bacillus licheniformis, Bacillus cereus, Lactobacillus acidophilus, Listeria monocytogenes, Staphylococcus aureus) and Gram-negative (Escherichia coli, Proteus vulgaris, Salmonella enterica) bacteria[2][16][17][18][19][20] and is also active against Chlamydia trachomatis.[21]

In Gram-positive bacteria, human PGLYRP4 binds to the separation sites of the newly formed daughter cells, created by bacterial peptidoglycan-lytic endopeptidases, LytE and LytF in B. subtilis, which separate the daughter cells after cell division.[17] These cell-separating endopeptidases likely expose PGLYRP4-binding muramyl peptides, as shown by co-localization of PGLYRP4 and LytE and LytF at the cell-separation sites, and no binding of PGLYRP4 to other regions of the cell wall with highly cross-linked peptidoglycan.[17] This localization is necessary for the bacterial killing, because mutants that lack LytE and LytF endopeptidases and do not separate after cell division, do not bind PGLYRP4, and are also not readily killed by PGLYRP4.[17]

The mechanism of bacterial killing by PGLYRP4 is based on induction of lethal envelope stress, which eventually leads to the shutdown of transcription and translation.[17] PGLYRP4-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.[17][18] PGLYRP4-induced oxidative and thiol stress involve malfunction of the respiratory electron transport chain in bacteria.[19][20][22] PGLYRP4-induced bacterial killing does not involve cell membrane permeabilization, which is typical for defensins and other antimicrobial peptides, cell wall hydrolysis, or osmotic shock.[2][16][17] Human PGLYRP4 has synergistic bactericidal activity with antibacterial peptides.[16]

Defense against infections

PGLYRP4 plays a limited role in host defense against infections. Intranasal administration of PGLYRP4 protects mice from lung infection with S. aureus and E. coli[2][23] and PGLYRP4-deficient mice are more sensitive to Streptococcus pneumoniae-induced pneumonia.[24]

Maintaining microbiome

Mouse PGLYRP4 plays a role in maintaining healthy microbiome, as PGLYRP4-deficient mice have significant changes in the composition of their intestinal microbiome,[7][24][25] which affects their increased sensitivity to lung inflammation and severity of S. pneumoniae-induced pneumonia.[24]

Effects on inflammation

Mouse PGLYRP4 plays a role in maintaining anti- and pro-inflammatory homeostasis in the intestine, skin, and lungs. PGLYRP4-deficient mice are more sensitive than wild type mice to dextran sodium sulfate (DSS)-induced colitis, which indicates that PGLYRP4 protects mice from DSS-induced colitis.[7]

PGLYRP4-deficient mice are also more sensitive than wild type mice to experimentally induced atopic dermatitis.[26] These results indicate that mouse PGLYRP4 is anti-inflammatory and protects skin from inflammation. This anti-inflammatory effect in the skin is due to decreased numbers and activity of T helper 17 (Th17) cells and increased numbers of T regulatory (Treg) cells.[26] PGLYRP4-deficient mice also have increased inflammatory responses in the lungs during S. pneumoniae-induced pneumonia associated with impaired bacterial clearance[24] and more severe pulmonary inflammation following Bordetella pertussis infection,[27] indicating anti-inflammatory role of PGLYRP4 in the lungs.

Medical relevance

Genetic PGLYRP4 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 PGLYRP4 gene (and also in the other three PGLYRP genes) than healthy controls.[10] PGLYRP4 variants are also associated with Parkinson’s disease,[28][29] psoriasis,[30][31] and ovarian cancer.[32] These results suggest that PGLYRP4 protects humans from these diseases, and that mutations in PGLYRP4 gene are among the genetic factors predisposing to these diseases. PGLYRP4 variants are also associated with the composition of airway microbiome.[33]

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 "Peptidoglycan recognition proteins: a novel family of four human innate immunity pattern recognition molecules". The Journal of Biological Chemistry 276 (37): 34686–34694. September 2001. doi:10.1074/jbc.M105566200. PMID 11461926. 
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 "Peptidoglycan recognition proteins are a new class of human bactericidal proteins". The Journal of Biological Chemistry 281 (9): 5895–5907. March 2006. doi:10.1074/jbc.M511631200. PMID 16354652. 
  3. ↑ "PGLYRP4 peptidoglycan recognition protein 4 [Homo sapiens (human) - Gene - NCBI"]. https://www.ncbi.nlm.nih.gov/gene/57115. 
  4. ↑ "PGLYRP4 - Peptidoglycan recognition protein 4 precursor - Homo sapiens (Human) - PGLYRP4 gene & protein" (in en). https://www.uniprot.org/uniprot/Q96LB8. 
  5. ↑ "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): 10078–10082. August 1998. doi:10.1073/pnas.95.17.10078. PMID 9707603. Bibcode: 1998PNAS...9510078K. 
  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): 1151–1163. June 2004. doi:10.1016/j.ygeno.2004.01.003. PMID 15177568. 
  7. ↑ 7.0 7.1 7.2 "Peptidoglycan recognition proteins protect mice from experimental colitis by promoting normal gut flora and preventing induction of interferon-gamma". Cell Host & Microbe 8 (2): 147–162. August 2010. doi:10.1016/j.chom.2010.07.005. PMID 20709292. 
  8. ↑ "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): 675–686. May 2005. doi:10.1111/j.1462-5822.2004.00500.x. PMID 15839897. 
  9. ↑ "The bacterial peptidoglycan-sensing molecule Pglyrp2 modulates brain development and behavior". Molecular Psychiatry 22 (2): 257–266. February 2017. doi:10.1038/mp.2016.182. PMID 27843150. 
  10. ↑ 10.0 10.1 "Genetic Association of Peptidoglycan Recognition Protein Variants with Inflammatory Bowel Disease". PLOS ONE 8 (6): e67393. 2013. doi:10.1371/journal.pone.0067393. PMID 23840689. Bibcode: 2013PLoSO...867393Z. 
  11. ↑ 11.0 11.1 "Human peptidoglycan recognition protein-L is an N-acetylmuramoyl-L-alanine amidase". The Journal of Biological Chemistry 278 (49): 49044–49052. December 2003. doi:10.1074/jbc.M307758200. PMID 14506276. 
  12. ↑ 12.0 12.1 12.2 12.3 12.4 "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): 8761–8766. May 2007. doi:10.1073/pnas.0701453104. PMID 17502600. Bibcode: 2007PNAS..104.8761C. 
  13. ↑ 13.0 13.1 "Crystal structure of human peptidoglycan recognition protein S (PGRP-S) at 1.70 A resolution". Journal of Molecular Biology 347 (4): 683–691. April 2005. doi:10.1016/j.jmb.2005.01.070. PMID 15769462. 
  14. ↑ 14.0 14.1 "Crystal structure of the C-terminal peptidoglycan-binding domain of human peptidoglycan recognition protein Ialpha". The Journal of Biological Chemistry 279 (30): 31873–31882. July 2004. doi:10.1074/jbc.M404920200. PMID 15140887. 
  15. ↑ "Structural basis for peptidoglycan binding by peptidoglycan recognition proteins". Proceedings of the National Academy of Sciences of the United States of America 101 (49): 17168–17173. December 2004. doi:10.1073/pnas.0407856101. PMID 15572450. Bibcode: 2004PNAS..10117168G. 
  16. ↑ 16.0 16.1 16.2 "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): 3116–3125. March 2007. doi:10.4049/jimmunol.178.5.3116. PMID 17312159. 
  17. ↑ 17.0 17.1 17.2 17.3 17.4 17.5 17.6 "Peptidoglycan recognition proteins kill bacteria by activating protein-sensing two-component systems". Nature Medicine 17 (6): 676–683. June 2011. doi:10.1038/nm.2357. PMID 21602801. 
  18. ↑ 18.0 18.1 "Peptidoglycan recognition proteins kill bacteria by inducing oxidative, thiol, and metal stress". PLOS Pathogens 10 (7): e1004280. July 2014. doi:10.1371/journal.ppat.1004280. PMID 25032698. 
  19. ↑ 19.0 19.1 "Bactericidal peptidoglycan recognition protein induces oxidative stress in Escherichia coli through a block in respiratory chain and increase in central carbon catabolism". Molecular Microbiology 105 (5): 755–776. September 2017. doi:10.1111/mmi.13733. PMID 28621879. 
  20. ↑ 20.0 20.1 "Formate dehydrogenase, ubiquinone, and cytochrome bd-I are required for peptidoglycan recognition protein-induced oxidative stress and killing in Escherichia coli". Scientific Reports 10 (1): 1993. February 2020. doi:10.1038/s41598-020-58302-1. PMID 32029761. Bibcode: 2020NatSR..10.1993K. 
  21. ↑ "Recombinant Human Peptidoglycan Recognition Proteins Reveal Antichlamydial Activity". Infection and Immunity 84 (7): 2124–2130. July 2016. doi:10.1128/IAI.01495-15. PMID 27160295. 
  22. ↑ "Respiratory chain components are required for peptidoglycan recognition protein-induced thiol depletion and killing in Bacillus subtilis and Escherichia coli". Scientific Reports 11 (1): 64. January 2021. doi:10.1038/s41598-020-79811-z. PMID 33420211. 
  23. ↑ "Mammalian peptidoglycan recognition proteins kill bacteria by activating two-component systems and modulate microbiome and inflammation". Microbial Drug Resistance 18 (3): 280–285. June 2012. doi:10.1089/mdr.2012.0002. PMID 22432705. 
  24. ↑ 24.0 24.1 24.2 24.3 "Peptidoglycan Recognition Protein 4 Limits Bacterial Clearance and Inflammation in Lungs by Control of the Gut Microbiota". Frontiers in Immunology 10: 2106. 2019. doi:10.3389/fimmu.2019.02106. PMID 31616404. 
  25. ↑ "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. doi:10.1371/journal.pone.0146162. PMID 26727498. Bibcode: 2016PLoSO..1146162D. 
  26. ↑ 26.0 26.1 "Differential effects of peptidoglycan recognition proteins on experimental atopic and contact dermatitis mediated by Treg and Th17 cells". PLOS ONE 6 (9): e24961. 2011. doi:10.1371/journal.pone.0024961. PMID 21949809. Bibcode: 2011PLoSO...624961P. 
  27. ↑ "Peptidoglycan Recognition Protein 4 Suppresses Early Inflammatory Responses to Bordetella pertussis and Contributes to Sphingosine-1-Phosphate Receptor Agonist-Mediated Disease Attenuation". Infection and Immunity 87 (2). February 2019. doi:10.1128/IAI.00601-18. PMID 30510103. 
  28. ↑ "Peptidoglycan recognition protein genes and risk of Parkinson's disease". Movement Disorders 29 (9): 1171–1180. August 2014. doi:10.1002/mds.25895. PMID 24838182. 
  29. ↑ "Single Nucleotide Polymorphisms Associated With Gut Homeostasis Influence Risk and Age-at-Onset of Parkinson's Disease". Frontiers in Aging Neuroscience 12: 603849. 2020-11-17. doi:10.3389/fnagi.2020.603849. PMID 33328979. 
  30. ↑ "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): 113–125. March 2006. doi:10.1007/s00439-005-0115-8. PMID 16362825. 
  31. ↑ "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): 109–115. February 2009. doi:10.1111/j.1600-0625.2008.00769.x. PMID 18643845. 
  32. ↑ "Next-generation sequencing-based genomic profiling analysis reveals novel mutations for clinical diagnosis in Chinese primary epithelial ovarian cancer patients". Journal of Ovarian Research 12 (1): 19. February 2019. doi:10.1186/s13048-019-0494-4. PMID 30786925. 
  33. ↑ "Host genetic variation in mucosal immunity pathways influences the upper airway microbiome". Microbiome 5 (1): 16. February 2017. doi:10.1186/s40168-016-0227-5. PMID 28143570. 

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