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Peptidoglycan recognition proteins in Drosophila melanogaster
Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The fruit fly Drosophila melanogaster is an excellent model organism to study the innate immune response, because insects and mammals share conserved features regarding the recognition and destruction of microorganisms and Drosophila is easily accessible to genetic manipulation. In my present study, I identified a new family of pattern recognition molecules for bacterial peptidoglycan in Drosophila, the Peptidoglycan Recognition Proteins (PGRP). This family of proteins is widespread in the animal kingdom, for instance there are 4 PGRP genes in humans with unknown function. So far, all tested PGRPs (from insects and mammals) have been shown to bind peptidoglycan. In Drosophila, we found and characterized 13 PGRP genes, which fall into two classes: Short PGRPs and Long PGRPs. To the short group belong PGRP-SA, SB1, SB2, SC1A, SC1B, SC2, and SD with short transcripts and predicted extracellular proteins. The long members are PGRP-LA, LB, LC, LD, LE, and LF with long transcripts and predicted intracellular and membrane spanning proteins. Transcripts from the 13 different PGRP genes are present in immune competent organs, and the majority are inducible by infection. The transcriptional regulation of the inducible PGRP genes occurs either via the imd/Relish or in some cases Toll/Dif pathway. My RNAi experiments in mbn-2 cells revealed that the peptidoglycan recognition protein PGRP-LC is a major activator of the imd/Relish pathway. In PGRP-LC deficient mbn-2 cells, Relish signalling is almost entirely blocked. However, the complex PGRP-LC gene generates three alternative splice forms, each of them carrying one of three possible PGRP domains, LCx, LCy, and LCa. I found that in the tissue culture system PGRP-LCa plays a specific role in the recognition of Gram-negative bacteria, while PGRP-LCx is crucial for the recognition of Gram-positive and Gram-negative bacteria, and peptidoglycan. Targeted mutagenesis of the PGRP-LCa isoform in vivo shows that the situation is more complicated than in the cell culture experiments. In conclusion, PGRPs constitute a highly diversified family of proteins, including key players of the innate immune response.

Place, publisher, year, edition, pages
Umeå: Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten) , 2004. , 58 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 0346-6612-922
Keyword [en]
Molecular biology, Drosophila, PGRP, peptidoglycan, pattern recognition, imd, Relish, isoform, RNAi, mbn-2
Keyword [sv]
Molekylärbiologi
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-355ISBN: 91-7305-741-X (print)OAI: oai:DiVA.org:umu-355DiVA: diva2:143213
Public defence
2004-11-30, Sal Betula, NUS, 901 87, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2004-11-09 Created: 2004-11-09 Last updated: 2011-04-11Bibliographically approved
List of papers
1. A family of peptidoglycan recognition proteins in the fruit fly Drosophila melanogaster.
Open this publication in new window or tab >>A family of peptidoglycan recognition proteins in the fruit fly Drosophila melanogaster.
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2000 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 97, no 25, 13772-13777 p.Article in journal (Refereed) Published
Abstract [en]

Peptidoglycans from bacterial cell walls trigger immune responses in insects and mammals. A peptidoglycan recognition protein, PGRP, has been cloned from moths as well as vertebrates and has been shown to participate in peptidoglycan-mediated activation of prophenoloxidase in the silk moth. Here we report that Drosophila expresses 12 PGRP genes, distributed in 8 chromosomal loci on the 3 major chromosomes. By analyzing cDNA clones and genomic databases, we grouped them into two classes: PGRP-SA, SB1, SB2, SC1A, SC1B, SC2, and SD, with short transcripts and short 5'-untranslated regions; and PGRP-LA, LB, LC, LD, and LE, with long transcripts and long 5'-untranslated regions. The predicted structures indicate that the first group encodes extracellular proteins and the second group, intracellular and membrane-spanning proteins. Most PGRP genes are expressed in all postembryonic stages. Peptidoglycan injections strongly induce five of the genes. Transcripts from the different PGRP genes were found in immune competent organs such as fat body, gut, and hemocytes. We demonstrate that at least PGRP-SA and SC1B can bind peptidoglycan, and a function in immunity is likely for this family.

Keyword
Amino Acid Sequence, Animals, Animals; Genetically Modified, Carrier Proteins/chemistry/*metabolism, Cloning; Molecular, DNA; Complementary, Drosophila melanogaster/*genetics/immunology, Molecular Sequence Data, RNA; Messenger/genetics, Sequence Homology; Amino Acid
Identifiers
urn:nbn:se:umu:diva-17069 (URN)10.1073/pnas.97.25.13772 (DOI)11106397 (PubMedID)
Available from: 2007-10-28 Created: 2007-10-28 Last updated: 2011-04-11Bibliographically approved
2. Requirement of a peptidoglycan recognition protein (PGRP) in Relish activation and antimicrobial immune responses in Drosophila.
Open this publication in new window or tab >>Requirement of a peptidoglycan recognition protein (PGRP) in Relish activation and antimicrobial immune responses in Drosophila.
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2002 (English)In: Science, Vol. 296, no 12 April 2002, 359-362 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:umu:diva-4210 (URN)
Available from: 2004-11-09 Created: 2004-11-09 Last updated: 2011-04-08
3. Functional diversity of the Drosophila PGRP-LC gene cluster in the response to lipopolysaccharide and peptidoglycan.
Open this publication in new window or tab >>Functional diversity of the Drosophila PGRP-LC gene cluster in the response to lipopolysaccharide and peptidoglycan.
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2003 (English)In: J Biol Chem, ISSN 0021-9258, Vol. 278, no 29, 26319-22 p.Article in journal (Refereed) Published
Keyword
Alternative Splicing, Animals, Carrier Proteins/*genetics, Cell Line, Drosophila/drug effects/*genetics/immunology/microbiology, Drosophila Proteins/*genetics, Genes; Insect/drug effects, Gram-Negative Bacteria/pathogenicity, Gram-Positive Bacteria/pathogenicity, Lipopolysaccharides/pharmacology, Multigene Family/drug effects, Peptidoglycan/pharmacology, RNA Interference
Identifiers
urn:nbn:se:su:diva-20030 (URN)12777387 (PubMedID)
Available from: 2007-11-21 Created: 2007-11-21 Last updated: 2011-01-13Bibliographically approved

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