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A scavenger function for a Drosophila peptidoglycan recognition protein
Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
Stockholm University, Faculty of Science, Department of Genetics, Microbiology and Toxicology.
2003 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, Vol. 278, no 9, 7059-7064 p.Article in journal (Refereed) Published
Abstract [en]

Recent studies of peptidoglycan recognition protein (PGRP) have shown that 2 of the 13 Drosophila PGRP genes encode proteins that function as receptors mediating immune responses to bacteria. We show here that another member, PGRP-SC1B, has a totally different function because it has enzymatic activity and thereby can degrade peptidoglycan. A mass spectrometric analysis of the cleavage products demonstrates that the enzyme hydrolyzes the lactylamide bond between the glycan strand and the cross-linking peptides. This result assigns the protein as anN-acetylmuramoyl-l-alanine amidase (EC3.5.1.28), and the corresponding gene is thus the first of this class to be described from a eukaryotic organism. Mutant forms of PGRP-SC1B lacking a potential zinc ligand are enzymatically inactive but retain their peptidoglycan affinity. The immunostimulatory properties of PGRP-SC1B-degraded peptidoglycan are much reduced. This is in striking contrast to lysozyme-digested peptidoglycan, which retains most of its elicitor activity. This points toward a scavenger function for PGRP-SC1B. Furthermore, a sequence homology comparison with phage T7 lysozyme, also an N-acetylmuramoyl-l-alanine amidase, shows that as many as six of the Drosophila PGRPs could belong to this class of proteins.

Place, publisher, year, edition, pages
2003. Vol. 278, no 9, 7059-7064 p.
Identifiers
URN: urn:nbn:se:su:diva-20032DOI: 10.1074/jbc.M208900200PubMedID: 12496260OAI: oai:DiVA.org:su-20032DiVA: diva2:186557
Available from: 2007-11-21 Created: 2007-11-21 Last updated: 2010-01-11Bibliographically approved
In thesis
1. Peptidoglycan regulation of Drosophila immunity
Open this publication in new window or tab >>Peptidoglycan regulation of Drosophila immunity
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Innate immunity is an ancient defense system that distinguishes between self and non self and is present in both vertebrates and invertebrates. Peptidoglycan (PGN), a cell wall component shared by both gram-negative and gram-positive bacteria, is the major recognition molecule for the detection of bacteria in Drosophila. Peptidoglycan Recognition Proteins (PGRPs) are conserved from insect to mammals and bind PGN with high affinity. In Drosophila, distinct PGRPs provide essential signals upstream of the Toll and Imd pathways. This thesis concerns the recognition of PGN by PGRPs and the expression of antibacterial peptides from the Imd pathway.

The PGRP-LC locus encodes three splice forms, a, x, and y. PGRP-LCx and PGRP-LCa form heterodimers in the presence of monomeric PGN. We propose a model for activation of Imd where PGRP-LCx binds to monomeric PGN leading to dimerization with PGRP-LCa and activation of the Imd pathway. With polymeric PGN, PGRP-LCx dimers activate the Imd pathway.

Drosophila PGRP-SC1B has amidase activity and cleaves the PGN lactamyl bond between the glycan strand and the peptide. The digested material is less immunogenic than intact PGN or PGN digested by egg white lysozyme. We suggest PGRP-SC1B to be a scavenger of immunogenic PGN. Amino acid sequence homology predicts six of the Drosophila PGRPs as well as two vertebrate PGRPs to be amidases. Murine PGRP-L is expressed in the liver and was shown to have PGN degrading activity. We found that an earlier purified human serum amidase is in fact identical to PGRP-L.

Although PGN is a potential trigger of the insect immune system, the actual detection of PGN in vivo poses problems. In gram-negative bacteria, PGN is covered by an outer membrane. Using a cell line approach we demonstrate that bacteria can be recognized by the Imd pathway without the need of phagocytosis or contact between bacteria and cells. Instead growing bacteria release immune eliciting fragments of PGN nature.

Place, publisher, year, edition, pages
Stockholm: Department of Genetics, Microbiology and Toxicology, Stockholm University, 2009. 50 p.
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Genetics
Identifiers
urn:nbn:se:su:diva-29828 (URN)978-91-7155-938-8 (ISBN)
Public defence
2009-10-23, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (English)
Opponent
Supervisors
Note
At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Submitted.Available from: 2009-10-01 Created: 2009-09-15 Last updated: 2009-09-17Bibliographically approved
2. Peptidoglycan Recognition Proteins: Major Regulators of Drosophila Immunity
Open this publication in new window or tab >>Peptidoglycan Recognition Proteins: Major Regulators of Drosophila Immunity
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

All eukaryotic organisms have an innate immune system characterized by germ-line encoded receptors and effector molecules, which mediate detection and clearance of microbes such as bacteria, fungi, and parasites. VertebrateDrosophila as a genetically tractable organism with a

This thesis concerns the peptidoglycan recognition protein (PGRP) gene family in the fruit fly. The family consists of thirteen genes, of which a few have been reported to be part of the signaling pathways that regulates immune

Data presented show that the putative receptors have affinity for peptidoglycan, but not for lipopolysaccharide, or the fungal cell wall polymer beta-glucan. PGRP-SA, receptor of the Toll pathway, has a preference for

In a search for novel PGRP receptors I found two PGRP proteins that instead displayed enzymatic activity towards peptidoglycan. They are of the N-actylmuramoyl L-alanine amidase type, which degrades peptidoglycan by splittingStaphylococcus aureus peptidoglycan looses its immune elicitor capacity. This is in contrast to lysozyme-degraded peptidoglycan, which isDrosophila PGRPs to be potential enzymes. PGRP-SB1 is the other enzymatic PGRP described within this thesis. It has a moreBacillus megaterium.

In conclusion, receptor PGRP proteins binds bacterial peptidoglycan and triggers immune gene pathways and enzymatic PGRPs have the capacity to reduce the elicitor property of peptidoglycan.

Place, publisher, year, edition, pages
Stockholm: Institutionen för genetik, mikrobiologi och toxikologi, 2005. 58 p.
Keyword
Innate immunity, peptidoglycan recognition protein, PGRP, Toll, Imd, Drosophila immunity
National Category
Pathobiology
Identifiers
urn:nbn:se:su:diva-646 (URN)91-7155-105-0 (ISBN)
Public defence
2005-09-28, De Geersalen, Geovetenskapens hus, Svante Arrhenius väg 8 A, Stockholm, 13:00 (English)
Opponent
Supervisors
Available from: 2005-09-06 Created: 2005-09-06 Last updated: 2010-01-11Bibliographically approved

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