Target and Pathway Deconvolution

Ligand-receptor and small molecule-protein interactions trigger cell type- and context-specific immune functions. The molecular mechanisms how immune activation and inhibition is sensed by receptors of endogenous and pattern recognition receptor-ligands and processed intracellularly is, however, often unknown. A prominent example is the still enigmatic activation of the NLRP3 inflammasome.

Intracellular signaling cascades are tightly regulated by rearrangements of protein networks governed by covalent and often reversible post-translational protein modifications (PTMs), as well as by interactions and translocations of distinct sets of proteins. Experimental approaches that quantitatively capture dynamic signaling networks are therefore valuable for establishing causal links to cellular phenotypes and developing strategies for targeted interference.

We employ a combination of proteomics methods to dissect intracellular immune signaling mechanisms. Focussing on PTMs, we have revealed novel intracellular immune signaling checkpoints such as the dephosphorylation of NLRP3 together with Eicke’s lab (Stutz et al 2017) and the ISG15ylation of TRAF2 (Frauenstein et al 2021). We further use proteomics target deconvolution, including thermal proteome profiling as powerful methods to identify direct targets of immune activators and inhibitors, and biochemical fractionation to unbiasedly map intracellular protein network rearrangements (Meissner et al 2022 in press).