Innate immune response
Signalling in the innate immune response
Invading pathogens are rapidly sensed by the hosts' innate immune system. The molecular mechanisms underlying pathogen detection and the subsequent cellular responses are rapidly being unveiled, but major knowledge gaps still remain. We focus on the initial steps after activation of the Toll-like receptors (TLRs).
Toll-like receptors (TLRs) are transmembrane receptors that recognize pathogen-associated molecular patterns (PAMPs), molecular signatures which are conserved in pathogens, such as lipopolysaccharides of gram-negative bacteria or viral RNA. TLRs play a central role in innate immunity: recognition of specific PAMPs leads to the activation of immune cell responses including phagocytosis, apoptosis, or the production of cytokines or interferons. They function as homo- or heterodimers or possibly as oligomers. They are characterized by the presence of extracellular Leucine Rich Repeats involved in PAMP recognition and intracellular Toll/IL-1 receptor-like (TIR) domains. Ligand-dependent activation of the TLRs leads to a cascade of intracellular protein-protein interactions involving a set of adapter proteins that ultimately leads to the appropriate cellular effects. We combine MAPPIT with mutagenesis and structural data to map the interfaces of protein interactions in the TLR pathway. With FACS- and Array-MAPPIT, we screen for new interaction partners in the TLR signalling pathways.
Related publications:
- Ulrichts et al. MAPPIT analysis of TLR adaptor complexes. FEBS Lett. (2007)
- Ulrichts and Tavernier. MAPPIT analysis of early Toll-like receptor signalling events. Immunol. Lett. (2008)
- Verstrepen et al. TLR-4, IL-1R and TNF-R signaling to NF-kappaB: variations on a common theme. Cell Mol. Life Sci. (2008)
- Ulrichts et al. Caspase-1 targets the TLR adaptor Mal at a crucial TIR-domain interaction site. J. Cell Sci. (2010)
- Bovijn et al. Identification of interaction sites for dimerization and adapter recruitment in Toll/interleukin-1 receptor (TIR) domain of Toll-like receptor 4. J. Biol. Chem. (2012)
- Bovijn et al. Identification of binding sites for myeloid differentiation primary response gene 88 (MyD88) and Toll-like receptor 4 in MyD88 adapter-like (Mal). J. Biol. Chem. (2013)
- Van Acker et al. The small GTPase Arf6 is essential for the Tram/Trif pathway in TLR4 signaling. J. Biol. Chem. (2014)
- Vyncke et al. Reconstructing the TIR Side of the Myddosome: a Paradigm for TIR-TIR Interactions. Structure (2016)
- Sikora et al. Germline gain-of-function myeloid differentiation primary response gene-88 (MYD88) mutation in a child with severe arthritis. J. Allergy Clin. Immunol. (2018)
- Van Acker et al. The Small GTPase Arf6: An Overview of Its Mechanisms of Action and of Its Role in Host⁻Pathogen Interactions and Innate Immunity. Int. J. Mol. Sci. (2019)
