1496Biochemical Society Transactions (2007) Volume 35, part 6
Peptidoglycan recognition in Drosophila
K. Aggrawal and N. Silverman1
Division of Infectious Diseases, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01720, U.S.A.
Drosophila rely primarily on innate immune responses to effectively combat a wide array of microbial
pathogens. The hallmark of the Drosophila humoral immune response is the rapid production of AMPs
(antimicrobial peptides) by the fat body, the insect homologue of the mammalian liver. Production of
these AMPs is controlled at the level of transcription by two NF-κB (nuclear factor κB) signalling pathways.
The Toll pathway is activated by fungal and many Gram-positive bacterial microbes, whereas the IMD
(immune deficiency) pathway responds to Gram-negative bacteria and certain Gram-positive bacilli. In the
present review, we discuss the mechanisms involved in bacterial recognition, in particular the differential
recognition of various types of bacterial PGN (peptidoglycan) by different members of the PGRP (PGN recog-
nition protein) family of receptors.
PGN (peptidoglycan) is the major structural component
of the cell wall of almost all bacterial species. PGN is a
large, repetitive macromolecule that forms the rigid cell wall
sacculus of bacteria. The basic unit of PGN is a disaccharide
(GlcNAc-MurNAc) with short peptides covalently attached
to the lactyl group of MurNAc. These stem-peptides include
both L- and D-amino acids and are not generated by the ri-
bosomes, but are instead synthesized by specialized enzymes
that are often targets of antibiotics. The stem-peptides can
also be cross-linked to one another by direct peptide bonds
or short cross-linking peptides . The enzymes responsible
As bacterial pathogens, but not eukaryotic hosts, produce
large amounts of PGN, this microbial product fits the main
criteria suggested by Janeway , in his seminal paper, that
pathogens. In fact, the stimulation of immune responses by
ago, in the analysis of the adjuvanticity of mycobacterial
cell wall products. MDP (muramyl-dipeptide), consisting
of muramic acid-L-alanine-iso-γ-glutamate, was the first
minimal PGN fragment identified based on its capacity
to stimulate an immune response. More recently, several
PGN-derived products have been linked to the activation of
innate immune responses in mammals and insects.
Insects, such as the fruitfly Drosophila melanogaster, lack
a classical adaptive immune system and rely primarily on
an innate immune response to combat microbial pathogens.
Key words: antimicrobial peptide, Drosophila, Gram-negative bacterium, Gram-positive
bacterium, innate immune response, peptidoglycan, Toll pathway.
Abbreviations used: AMP, antimicrobial peptide; DAP, diaminopimelic acid; GNBP, Gram-
negative binding protein; IMD, immune deficiency; MDP, muramyl-dipeptide; MyD88, myeloid
differentiation factor 88; NF-κB, nuclear factor κB; NOD, nucleotide-binding oligomerization
domain; NLR, NOD-like receptor; PGN, peptidoglycan; PGRP, PGN recognition protein; RIP,
receptor-interacting protein; RHIM, RIP homotypic interaction motif; SPE, Sp¨ atzle processing
enzyme; TCT, tracheal cytotoxin; TIR, Toll/interleukin-1 receptor; TLR, Toll-like receptor; TRIF, TIR
domain-containing adaptor protein inducing interferon β.
1To whom correspondence should be addressed (email firstname.lastname@example.org).
Even without the aid of antibodies and T-cells, the insect
immune response is highly effective and is able to withstand
infections with many different types of microbes. One
primary mechanism that insects use to control microbes is
the inducible productionof a battery of AMPs (antimicrobial
to recognize bacterial pathogens and induce expression
of AMP genes. The IMD (immune deficiency) pathway
responds to all Gram-negative bacteria, whereas the Toll
pathway (Figure 1) preferentially recognizes many Gram-
have demonstrated that both the IMD and Toll pathways
are stimulated by PGN, but differences in PGN structure
(diaminopimelic acid) at the third position of the stem-
peptide, which is found in all Gram-negative bacteria and
certain Gram-positives (such as Bacillus spp. and Listeria
monocytogenes), activates the IMD pathway, while lysine-
type PGN, found in most other Gram-positive bacteria,
stimulates the Toll pathway [7,8]. Surprisingly, lipopolysac-
does not activate the IMD pathway although it is a potent
activator of mammalian innate immunity .
PGN recognition in the Drosophila is mediated by the
PGRP (PGN recognition protein) family of receptors.
Drosophila have 13 PGRP genes which encode approx. 17
PGRP proteins, through alternative splicing. The PGRP
domain is similar in structure to type 2 bacteriophage
amidases (N-acetylmuramoyl-L-alanine amidases), enzymes
that cleave the amide bond connecting the stem-peptide to
the carbohydrate backbone of PGN. In fact, some PGRPs
have amidase activity and are capable of digesting PGN,
while others lack a critical cysteine residue that is part of
the catalytic triad, and function instead as PGN-binding
receptors . The Drosophila PGRPs can also be categorized
C ?The Authors Journal compilation
C ?2007 Biochemical Society
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