Immune Signaling Pathways
The
main goal of our lab is to decipher the molecular mechanisms responsible for
transmitting a signal from the site of infection to the nucleus of an immune
responsive cell. We are interested in how pathogens are distinguished, how related
signaling pathways maintain specificity, and how various signals are integrated
to produce the proper response. Research will focus on the immune response of
the experimentally powerful fruit fly, Drosophila melanogaster. We are
particularly interested in the mechanisms used in Drosophila that allow
distinct pathogenic challenges to lead to specific immune responses by activating
different signaling pathways and transcription factors. The immune signaling
pathways in Drosophila have much in common with the pathways required
for the activation of the mammalian innate immune response. In fact, the Toll-like
receptor (TLR) family, which was discovered in Drosophila, plays
a central role in pathogen recognition in both mammals and insects. A deeper
understanding of these pathways in insects will undoubtedly lead to further
advances in related mammalian fields.
The Drosophila antibacterial
signaling pathway |
In flies, infection causes the rapid production of a host of powerful antimicrobial
peptides that are produced in the fat body (the insect liver) and ciruculate
throughout the body. Pathogens are known to activate two separate and specific
immune response signaling pathways, an antibacterial and an antifungal pathway,
each of which culminates in the activation of different Drosophila NF-kB
transcription factors. Fungal infection leads to the activation of Toll, which
initiates a signal transduction cascade leading to the proteasome-mediated degradation
of Cactus (the fly IkB), the nuclear
translocation of two Drosophila NF-kB
transcription factors, Dif and Dorsal, and the rapid expression of antifungal
peptide genes. The Toll signaling pathway is also essential for the dorsoventral
patterning of the developing embryo. The third Drosophila NF-kB
protein, Relish, is required for antibacterial immunity. Relish is initially
synthesized as a bipartite protein with an N-terminal NF-kB-like
domain and C-terminal IkB-like domain,
which inhibits its own nuclear translocation. Upon infection Relish is cleaved,
freeing the NF-kB module to translocate
to the nucleus where it activates antibacterial peptide gene expression.
Our lab is focused upon understanding the molecular mechanisms responsible for
the activation of these two NF-kB pathways
during the insect immune response. The antibacterial pathway, which is controlled
by Relish, requires the Drosophila IkB
kinase complex (IKK), a high molecular weight complex which contains a catalytic
subunit, DmIKKb, and regulatory subunit,
DmIKKg. Upon infection, the Drosophila
IKK complex is activated and is required for the cleavage (and activation) of
Relish. We are interested to know what lies upstream of the Drosophila
IKK complex, what receptors are used to recognize pathogens and how does activation
of these receptors, in turn, lead to the activation of the IKK complex. The
mechanism of DmIKK-stimulated Relish cleavage is also a major focus in the laboratory.
The Drosophila Toll/antifungal
signaling pathway |
The antifungal pathway, which relies on the classic Toll signaling pathway,
is also a focus of our research. Although we know a great deal about this signaling
pathway, many important questions remain. In particular, we are interested in
mechanisms of signal-induced Cactus degradation. Like mammalian IkBs,
Cactus is phosphorylated upon signaling and this signaling leads to its proteasome
mediated degradation. However, unlike IkB,
Cactus degradation does not require the IKK complex, and the identity of the
Cactus kinase is currently unknown.
Our goal is to uncover the molecular mechanism used by the innate immune system
to recognize dangerous microbes and to rapidly mount a potent and specific response
against them. Using Drosophila, with its powerful genetic, molecular, and biochemical
tools, will enable us to gain a thorough understanding of the signal transduction
pathways used by eukaryotes to fend-off their adversaries. This research has
potential medical benefits beyond its primary goal of basic scientific understanding.
A deeper understanding of the insect immune response will enable the design
of new methods to combat the spread of infectious microbes by insects. Moreover,
the similarities between the insect immune response and mammalian innate immunity
will open-up new and exciting avenues of research into the mechanisms which
control our more complicated immune response.
Also Vist:
The
Silverman Lab
