Alternative titles; symbols
HGNC Approved Gene Symbol: PGLYRP1
Cytogenetic location: 19q13.32 Genomic coordinates (GRCh38) : 19:46,019,153-46,023,053 (from NCBI)
Innate nonself immune recognition relies on structures common among invading microbes, a process termed pattern recognition. Peptidoglycan is a fundamental component of the bacterial cell wall and is thus a candidate for a pattern recognized by the immune system. Using differential display to identify bacteria-induced genes in the moth Trichoplusia ni, Kang et al. (1998) cloned a cDNA encoding the T. ni peptidoglycan (PGN) recognition protein (PGRP, or PGLYRP). Recombinant T. ni PGLYRP bound to PGN and to gram-positive bacteria. By PCR of human and mouse spleen cDNAs, they isolated human and mouse PGLYRP cDNAs, respectively. The deduced human PGLYRP protein has 196 amino acids. Both the human and mouse PGLYRP proteins share 43% sequence identity with the T. ni PGLYRP protein. Recombinant mouse Pglyrp protein expressed in insect cells possessed an affinity for PGN. Dot blot analysis of a number of human tissue mRNAs detected strong expression in bone marrow and weak expression in lung, kidney, liver, small intestine, spleen, thymus, peripheral leukocyte, and fetal spleen.
Liu et al. (2001) cloned PGLYRP, which they called PGRPS, by PCR of a bone marrow cDNA library. The deduced 196-amino acid protein contains an N-terminal signal peptide, followed by the extracellular PGRP domains III, II, and I, which are highly conserved in mammalian and insect PGRPs. PGRPS shares 40%, 43%, and 42% amino acid identity with PGRPL (608199), PGRPI-alpha (PGLYRP3; 608197), and PGRPI-beta (PGLYRP4; 608198). RNA dot blot analysis detected strong PGRPS expression in bone marrow and expression that was 50 to 100 times lower in polymorphonuclear leukocytes and fetal liver. Northern blot analysis detected 1.4-, 0.9-, and 0.5-kb transcripts in bone marrow, a 0.9-kb transcript in fetal liver, and 1.4- and 0.9-kb transcripts in peripheral blood leukocytes. PCR detected low expression of PGRPS in spleen, jejunum, and thymus, possibly due to the presence of polymorphonuclear leukocytes in these tissues. Transiently transfected COS-7 and human embryonic kidney cells expressed PGRPS as a protein with an apparent molecular mass of 24 kD. About half of the expressed PGRPS was detected in the culture medium, and the remainder was a Triton X-100-soluble membrane protein.
Liu et al. (2001) determined that recombinant PGRPS expressed by COS-7 cells and human embryonic kidney cells bound to gram-positive bacteria, B. subtilis and M. luteus, with high affinity.
Using purified PGLYRP1, PGLYRP3, PGLYRP4, and a PGLYRP3/PGLYRP4 heterodimer, Kashyap et al. (2011) showed that these PGRPs interacted with the bacterial cell wall and activated bacterial 2-component systems, resulting in membrane depolarization, cessation of PGN, protein, DNA, and RNA synthesis, and production of hydroxyl radicals to cause bacterial death. Fluorescence microscopy demonstrated that, in B. subtilis, a gram-positive bacteria, PGRPs entered the cell wall at the site of daughter cell separation during cell division and activated the CssR-CssS 2-component system. In E. coli, a gram-negative bacteria, PGRPs bound the outer membrane and activated the CpxA-CpxR 2-component system. Kashyap et al. (2011) excluded other bactericidal mechanisms, including inhibition of PGN synthesis, PGN hydrolysis, and membrane permeabilization. They concluded that PGRPs are innate immunity proteins that bind the cell wall or outer membrane and exploit the bacterial stress response to kill bacteria.
Read et al. (2015) found that stimulation of human neutrophils with a mixture of TLR ligands triggered TREM1 (605085) in a reporter cell line, whereas stimulation with TLR ligands in the absence of neutrophils failed to induce TREM1 activation. Peptidoglycan (PGN) turned out to be the critical TLR ligand for TREM1 induction. Mass spectrometric and immunoprecipitation analyses identified PGLYRP1 as the TREM1-stimulating protein on neutrophils cultured with PGN. Addition of PGLYRP1 to PGN enabled PGN recognition by TREM1. Blockade of either TREM1 or PGLYRP1 inhibited IL8 (146930) release. Surface plasmon resonance analysis indicated that PGN enhanced and stabilized the interaction of TREM1 with PGLYRP1. Activation of TREM1 by PGLYRP1 required multimeric PGN. In the absence of bacterial products, TREM1 on myeloid cells could also be activated by multimeric PGLYRP1.
Using a yeast library screen, Gupta et al. (2020) found that human PGLYRP1 interacted with most of 36 isolates of Borrelia burgdorferi, the spirochete that causes Lyme disease. Subsequent experiments showed that recombinant human PGLYRP1 interacted with purified peptidoglycan from the spirochete. Infected Pglyrp1-knockout mice had increased spirochete burden in heart and joints, splenomegaly, and signs of immune dysregulation.
Liu et al. (2001) determined that the PGLYRP gene contains 3 exons.
By genomic sequence analysis, Liu et al. (2001) mapped the PGLYRP1 gene to chromosome 19. Gross (2015) mapped the PGLYRP1 gene to chromosome 19q13.32 based on an alignment of the PGLYRP1 sequence (GenBank BC096154) with the genomic sequence (GRCh38).
Gross, M. B. Personal Communication. Baltimore, Md. 12/28/2015.
Gupta, A., Arora, G., Rosen, C. E., Kloos, Z., Cao, Y., Cerny, J., Sajid, A., Hoornstra, D., Golovchenko, M., Rudenko, N., Munderloh, U., Hovius, J. W., Booth, C. J., Jacobs-Wagner, C., Palm, N. W., Ring, A. M., Fikrig, E. A human secretome library screen reveals a role for peptidoglycan recognition protein 1 in Lyme borealis. PLoS Pathog. 16: e1009030, 2020. [PubMed: 33175909] [Full Text: https://doi.org/10.1371/journal.ppat.1009030]
Kang, D., Liu, G., Lundstrom, A., Gelius, E., Steiner, H. A peptidoglycan recognition protein in innate immunity conserved from insects to humans. Proc. Nat. Acad. Sci. 95: 10078-10082, 1998. [PubMed: 9707603] [Full Text: https://doi.org/10.1073/pnas.95.17.10078]
Kashyap, D. R., Wang, M., Liu, L.-H., Boons, G.-J., Gupta, D., Dziarski, R. Peptidoglycan recognition proteins kill bacteria by activating protein-sensing two-component systems. Nature Med. 17: 676-683, 2011. [PubMed: 21602801] [Full Text: https://doi.org/10.1038/nm.2357]
Liu, C., Xu, Z., Gupta, D., Dziarski, R. Peptidoglycan recognition proteins: a novel family of four human innate immunity pattern recognition molecules. J. Biol. Chem. 276: 34686-34694, 2001. [PubMed: 11461926] [Full Text: https://doi.org/10.1074/jbc.M105566200]
Read, C. B., Kuijper, J. L., Hjorth, S. A., Heipel, M. D., Tang, X., Fleetwood, A. J., Dantzler, J. L., Grell, S. N., Kastrup, J., Wang, C., Brandt, C. S., Hansen, A. J., Wagtmann, N. R., Xu, W., Stennicke, V. W. Cutting edge: identification of neutrophil PGLYRP1 as a ligand for TREM-1. J. Immun. 194: 1417-1421, 2015. [PubMed: 25595774] [Full Text: https://doi.org/10.4049/jimmunol.1402303]