Jonathan C. Kagan
Ancient signaling pathways lie at the base of the initiation of immunity, serving to transmit signals from Pattern Recognition Receptors (PRRs) to trigger the activation of anti-microbial defenses. All PRRs, which evolved to detect potentially pathogenic microorganisms, operate by following two cellular rules: 1) these receptors must activate cytosolic signaling with extremely fast kinetics (within seconds of ligand binding) 2) these receptors must survey multiple cellular compartments, yet still recruit a common set of signaling proteins to each location. How does a signaling network develop that has properties of near immediate responsiveness, yet the flexibility to signal from multiple locations?
While most research on immune signal transduction focuses on the effector functions of signaling proteins, we are interested in understanding how these proteins are organized in the cytosol to promote both rapid responses and the flexibility of signaling locale. Using the Toll-like Receptor (TLR) and RIG-I like Receptor (RLR) families of PRRs as models, we seek to explain the operation of cytosolic signaling proteins that function in immune defense.
TLRs and RLRs promote the initiation of both innate and adaptive immunity to infectious microorganisms and as such, the regulation of their signaling functions lies at the base of important issues in human health, such as the generation of effective vaccines, autoimmunity, and cancer.
Understanding the fundamental cellular principles that control TLR/RLR signaling will likely reveal important insight into these problems and will open up new possibilities for treatment of common ailments that affect humanity.
Current projects in the lab focus on addressing the following problems:
1. How are TLR and RLR signaling proteins delivered to the appropriate cellular locations to promote signal transduction?
2. What are the biochemical properties of TLR/RLR-induced signaling complexes?
3. How does the innate immune response deal with commensal bacteria in the intestine?
Phosphoinositide Binding by the Toll Adaptor dMyD88 Controls Antibacterial Responses in Drosophila.
Marek LR, Kagan JC.
Immunity. 2012 Apr 20;36(4):612-22.
CD14 controls the LPS-induced endocytosis of Toll-like receptor 4.
Zanoni I, Ostuni R, Marek LR, Barresi S, Barbalat R, Barton GM, Granucci F, Kagan JC.
Cell. 2011 Nov 11;147(4):868-80.
Peroxisomes are signaling platforms for antiviral innate immunity. Dixit E, Boulant S, Zhang Y, Lee AS, Odendall C, Shum B, Hacohen N, Chen ZJ, Whelan SP, Fransen M, Nibert ML Superti-Furga G, Kagan JC. Cell. 2010 May 14;141(4):668-81.
A cell biological view of Toll-like receptor function: regulation through compartmentalization. Barton GM, Kagan JC. Nat Rev Immunol. 2009 Aug;9(8):535-42.
Last Update: 1/6/2014