Abstract

Higher-order oligomeric assembly in the innate immune system: Myddosome assembly and the induction of inflammation

The Myddosome is a specialized innate immune signaling complex that activates NF-kB signaling. Critical to NF-kB activation is the formation of lysine-63 and methionine-1 linked polyubiquitin chains. How does the Myddosome control the formation of these two distinct polyubiquitin chains to activate NF-kB signaling? In this talk, I will describe how we have discovered that Myddosomes are plasma membrane-tethered organelles that concentrate and activate the protein machinery that assembles K63 /M1 polyubiquitin chains. We discovered that the spatial reorganization of Myddosomes into clusters regulates the formation of M1/K63 ubiquitin chains and the activation of NF-kB signaling. Inhibiting Myddosome clustering reduced the recruitment of the K63 ubiquitin ligases TRAF6 and the M1 ubiquitin ligase HOIL1 . Finally, I will describe our efforts to create a spatial and temporal map of the IL-1-Myddosome signaling network. These efforts seek to understand how extracellular signalling triggers the assembly of the Myddosome and how the stoichiometric composition of oligomeric signaling complexes remodels in time.