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Communicate or die: signalling in Drosophila immunity
Umeå University, Faculty of Medicine, Umeå Centre for Molecular Pathogenesis (UCMP) (Faculty of Medicine).
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In general the work behind this thesis has revolved around the interesting pattern recognition gene family PGRPs (peptidoglycan recognition proteins). In particular the transmembrane PGRP-LC and to investigate its multifaceted role in the immune response of the fruit fly. As a well characterized model organism living on, and surrounded by, a multitude of microorganisms, Drosophila melanogaster serves as a great tool to gain insights about innate immunity. The two pillars of Drosophila innate immunity are the humoral and the cellular defense. Together they are very potent and can vanquish many infections, but if one of these pillars is damaged, chances are that the defense will collapse and the organism will succumb to the infection.

The initial step in any immune response is to become aware of the pathogen. To accomplish this, innate immunity relies on recognizing common molecular building blocks necessary each group of microorganisms. One such building block is the bacterial cell wall component peptidoglycan. PGRPs are a widely spread gene family, and proteins of this family can bind peptidoglycan. We describe that there are 13 PGRP genes in Drosophila, one these codes for PGRP-LC. As it sits in the cell membrane in any of its three different splice forms, PGRP-LC can bind peptidoglycan, dimerize, and subsequently activate the imd/relish signalling pathway, and thereby trigger a vast production of antimicrobial peptides. These short peptides are the firearms of the humoral response. We identified three new inducible antimicrobial peptide genes, Diptericin B, Attacin C and Attacin D. Analyses of their sequences shed light on the evolution and relationship of these antimicrobial peptides

The antimicrobial peptides are potent weapons, but without a functional cellular response the animal is at loss. Animals lacking blood cells are gravely compromised. It is interesting to find that PGRP-LC is involved at this end of the immune response equation as well. We have found that PGRP-LC is able to activate blood cells and increase numbers of circulating cells, in a JNK (Jun N-terminal kinase) dependent manner. Intriguingly this activation is not dependent on Relish, the NF-kB transcription factor of the Imd/Relish pathway.

PGRP-LC activation funnels into both Imd/Relish and the JNK pathways. When PGRP-LC is lost, it appears that some basal, or background, JNK activation is lost. These effects are very mild, however the animal appears to become more sensitive to additional perturbations in this signalling pathway. This was the starting point when we started to re-evaluate Dredd, the caspase responsible for cleaving and activating Relish. Dredd also contributes to the JNK signalling pathway.

Place, publisher, year, edition, pages
Umeå: Umeå centrum för molekylär patogenes (UCMP) (Medicinska fakulteten) , 2008. , 63 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1187
Keyword [en]
Drosophila, innate immunity, PGRP-LC, pattern recognition, JNK, antimicrobial peptides
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-1817ISBN: 978-91-7264-619-3 (print)OAI: oai:DiVA.org:umu-1817DiVA: diva2:142094
Public defence
2008-09-26, KB3A9, KBC, Umeå Universitet, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2008-09-09 Created: 2008-09-09 Last updated: 2010-01-18Bibliographically approved
List of papers
1. 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
Show others...
2003 In: J. Biol. Chem., ISSN 0021-9258, Vol. 278, no 29, 26319-26322. p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:su:diva-24032 (URN)
Note
Part of urn:nbn:se:su:diva-646Available from: 2005-09-06 Created: 2005-09-06Bibliographically approved
2. Expression and evolution of the Drosophila attacin/diptericin gene family.
Open this publication in new window or tab >>Expression and evolution of the Drosophila attacin/diptericin gene family.
2000 (English)In: Biochem Biophys Res Commun, ISSN 0006-291X, Vol. 279, no 2, 574-81 p.Article in journal (Refereed) Published
Abstract [en]

We describe the genes for three new glycine-rich antimicrobial peptides in Drosophila, two attacins (AttC and AttD) and one diptericin (DptB). Their structures support the proposal that these glycine-rich antimicrobial peptides evolved from a common ancestor and are probably also related to proline-rich peptides such as drosocin. AttC is similar to the nearby AttA and AttB genes. AttD is more divergent and located on a different chromosome. Intriguingly, AttD may encode an intracellular attacin. DptB is linked in tandem to the closely related Diptericin. However, the DptB gene product contains a furin-like cleavage site and may be processed in an attacin-like fashion. All attacin and diptericin genes are induced after bacterial challenge. This induction is reduced in imd mutants, and unexpectedly also in Tl(-) mutants. The 18w mutation particularly affects the induction of AttC, which may be a useful marker for 18w signaling.

Keyword
Amino Acid Sequence, Animals, Anti-Infective Agents/chemistry, Drosophila/classification/*genetics, Drosophila Proteins, Drosophila melanogaster/genetics, Evolution, Evolution; Molecular, Genes; Insect, Insect Proteins/chemistry/*genetics, Insects/classification/*genetics, Molecular Sequence Data, Multigene Family, Phylogeny, Protein Isoforms/chemistry/genetics, Sequence Alignment, Sequence Homology; Amino Acid
Identifiers
urn:nbn:se:umu:diva-17071 (URN)10.1006/bbrc.2000.3988 (DOI)11118328 (PubMedID)
Available from: 2007-10-28 Created: 2007-10-28Bibliographically approved
3. PGRP-LC activates blood cells through JNK, and not via relish
Open this publication in new window or tab >>PGRP-LC activates blood cells through JNK, and not via relish
Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-3410 (URN)
Available from: 2008-09-09 Created: 2008-09-09 Last updated: 2010-01-13Bibliographically approved
4. PGRP-LC and Dredd interact with JNK signalling in Drosophila development and immunity
Open this publication in new window or tab >>PGRP-LC and Dredd interact with JNK signalling in Drosophila development and immunity
Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-3411 (URN)
Available from: 2008-09-09 Created: 2008-09-09 Last updated: 2010-01-13Bibliographically approved
5. The Drosophila NFAT homolog is involved in salt stress tolerance.
Open this publication in new window or tab >>The Drosophila NFAT homolog is involved in salt stress tolerance.
2007 (English)In: Insect Biochem Mol Biol, ISSN 0965-1748, Vol. 37, no 4, 356-62 p.Article in journal (Refereed) Published
Abstract [en]

The NFAT gene encodes the only homolog in Drosophila of the five human Nuclear Factors of Activated T-cells, NFAT1-5. Its rel homology domain is most similar to that of NFAT5, and like the latter it lacks conserved AP1 and calcineurin binding sites. Two promoters give rise to alternative transcripts that are ubiquitously expressed in several different tissues. We generated mutants for each transcript, as well as a mutant that lacks all functional NFAT expression. Only the null mutant generated a visible phenotype, indicating that the two transcripts are redundant. The mutants are sensitive to high salt diet and have enlarged anal pads in hypotonic solution, suggesting that NFAT, like mammalian NFAT5, is regulating the osmotic balance. A phylogenetic reconstruction puts the Drosophila gene near the root of the NFAT tree, indicating that regulation of tonicity may be an ancestral function of the NFAT family.

Keyword
Adaptation; Physiological, Animals, Drosophila/genetics/metabolism/*physiology, Heat, Larva/metabolism, Melanins/metabolism, Mutation, NFATC Transcription Factors/genetics/metabolism/*physiology, Sodium Chloride/*metabolism
Identifiers
urn:nbn:se:umu:diva-17041 (URN)17368199 (PubMedID)
Available from: 2007-10-28 Created: 2007-10-28 Last updated: 2011-01-11Bibliographically approved

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