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Caspase-1 targets the TLR adaptor Mal at a crucial TIR-domain interaction site
- Source :
- Journal of cell science. 123(Pt 2)
- Publication Year :
- 2010
-
Abstract
- Toll-like receptors (TLRs) are crucial components of innate immunity, ensuring efficient responses against invading pathogens. After ligand binding, TLR signaling is initiated by recruitment of adaptor molecules, a step mediated by homotypic Toll-IL-1 receptor (TIR) domain interactions. Four TIR-containing TLR adaptor molecules are described, all of which are susceptible to modification and strict regulation. For example, caspase-1 is reported to cleave the TLR adaptor Mal at position D198, an event that is indispensible for Mal function. In this report, we use the mammalian two-hybrid technique MAPPIT to study the implications of Mal cleavage. We show that a Mal mutant, which mimics caspase-1 cleavage and a caspase-1-uncleavable MalD198A mutant, are abrogated in their bridging function and lose the ability to activate NF-κB. A MalD198E mutant is still fully functional, suggesting that caspase-1 cleavage of Mal is not necessary for Mal-mediated signaling. D198 of Mal is conserved in MyD88 and TLR4 TIR domains and the negatively charged amino acid at this position is crucial for the interactions and function of Mal, MyD88 and TLR4 TIR. Our data suggest an inhibitory, rather than an activating role for caspase-1 in Mal regulation, and show that the caspase-1 cleavage site in Mal is part of a TIR-domain interaction site.
- Subjects :
- Amino Acids, Acidic
Mutant
Molecular Sequence Data
Caspase 1
Biology
Cleavage (embryo)
Cell Line
Two-Hybrid System Techniques
Humans
Amino Acid Sequence
Conserved Sequence
Toll-like receptor
Innate immune system
Binding Sites
Membrane Glycoproteins
Toll-Like Receptors
NF-kappa B
Receptors, Interleukin-1
Cell Biology
NFKB1
Cell biology
Protein Structure, Tertiary
Toll-Like Receptor 4
Amino Acid Substitution
Mutation
Myeloid Differentiation Factor 88
TLR4
Mutant Proteins
Signal transduction
Protein Multimerization
Sequence Alignment
Protein Binding
Subjects
Details
- ISSN :
- 14779137
- Volume :
- 123
- Issue :
- Pt 2
- Database :
- OpenAIRE
- Journal :
- Journal of cell science
- Accession number :
- edsair.doi.dedup.....cb8f35abeae3eff33be25ea2b70ac63b