Research area 1: The NLRP1b Inflammasome
The efficacy of the innate immune system depends on its ability to mount an appropriate response to diverse infections and damaging agents.
Key components of this system are pattern recognition receptors that detect pathogen associated- and damage associated- molecular patterns (PAMPs and DAMPs).
We study a pattern recognition receptor, NLRP1b, that assembles into an inflammasome complex that activates caspase-1.
NLRP1b detects metabolic stress induced by glucose deprivation or by metabolic inhibitors, which leads to the reduction of cytosolic ATP levels.
We are investigating the processes that allow NLRP1b to detect metabolic stress and then assemble into a functional complex.
Research area 2: Anthrax Toxin
Anthrax toxin is comprised of two toxic enzymes and a third protein, PA, which assembles into a nanomachine that delivers the toxic enzymes to the interior of human cells.
We are studying two critical steps in the assembly of this translocation machine.
The first step we are studying is the binding of PA to receptors on human cells – this allows the toxin to target susceptible cells.
We have discovered that the extracellular part of the receptor exists in two different conformations and that only one of these conformations is able to bind toxin. Furthermore, we have shown that the receptor binds actin and that it is the binding of actin that switches the receptor from the conformation that binds toxin to the conformation that does not bind toxin.
We seek to determine how the binding to actin inside the cell is able to change the conformation of the receptor outside the cell.
The second step in the assembly process we are studying is the insertion of the toxin into the cell membrane.
This is an essential event because membrane insertion forms a hole through which the toxic enzymes pass to the cell interior.
The receptors stabilize the toxin until the toxin reaches an acidic region of the cell; the acidity breaks an interaction between the toxin and its receptor, which allows membrane insertion.
We are investigating how the receptor controls insertion of the toxin and the interactions that allow insertion to occur in a highly efficient manner.
Neiman-Zenevich J, LIao KC and Mogridge J (2014) Distinct regions of NLRP1B are required to respond to anthrax lethal toxin and metabolic inhibition. Infection and Immunity 82: 3967-3703
Dennis MK and Mogridge J (2014) A protective antigen mutation increases the pH threshold of anthrax toxin receptor 2-mediated pore formation. Biochemistry 53: 2166-2171
Liao KC and Mogridge J (2013) Activation of Nlrp1b inflammasome by reduction of cytosolic ATP. Infection and Immunity 81: 570-579
Frew B.C., Joag V.R., and Mogridge J. (2012) Proteolytic processing of Nlrp1b is required for inflammasome activity PLoS Pathogens 8: e1002659