Advanced search
1 file | 1.29 MB Add to list

Caspase-1 targets the TLR adaptor Mal at a crucial TIR-domain interaction site

Peter Ulrichts (UGent) , Celia Bovijn (UGent) , Sam Lievens (UGent) , Rudi Beyaert (UGent) , Jan Tavernier (UGent) and Frank Peelman (UGent)
(2010) JOURNAL OF CELL SCIENCE. 123(2). p.256-265
Author
Organization
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-kappa B. 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.
Keywords
MAPPIT ANALYSIS, ACTIVATION, STRUCTURAL BASIS, CRYSTAL-STRUCTURE, INTERFERON-BETA, SIGNAL-TRANSDUCTION, NF-KAPPA-B, TOLL-LIKE RECEPTOR, MYD88, MOLECULE, Caspase-1, Mal, TLR, TIR domain

Downloads

  • (...).pdf
    • full text
    • |
    • UGent only
    • |
    • PDF
    • |
    • 1.29 MB

Citation

Please use this url to cite or link to this publication:

MLA
Ulrichts, Peter, et al. “Caspase-1 Targets the TLR Adaptor Mal at a Crucial TIR-Domain Interaction Site.” JOURNAL OF CELL SCIENCE, vol. 123, no. 2, 2010, pp. 256–65, doi:10.1242/jcs.056002.
APA
Ulrichts, P., Bovijn, C., Lievens, S., Beyaert, R., Tavernier, J., & Peelman, F. (2010). Caspase-1 targets the TLR adaptor Mal at a crucial TIR-domain interaction site. JOURNAL OF CELL SCIENCE, 123(2), 256–265. https://doi.org/10.1242/jcs.056002
Chicago author-date
Ulrichts, Peter, Celia Bovijn, Sam Lievens, Rudi Beyaert, Jan Tavernier, and Frank Peelman. 2010. “Caspase-1 Targets the TLR Adaptor Mal at a Crucial TIR-Domain Interaction Site.” JOURNAL OF CELL SCIENCE 123 (2): 256–65. https://doi.org/10.1242/jcs.056002.
Chicago author-date (all authors)
Ulrichts, Peter, Celia Bovijn, Sam Lievens, Rudi Beyaert, Jan Tavernier, and Frank Peelman. 2010. “Caspase-1 Targets the TLR Adaptor Mal at a Crucial TIR-Domain Interaction Site.” JOURNAL OF CELL SCIENCE 123 (2): 256–265. doi:10.1242/jcs.056002.
Vancouver
1.
Ulrichts P, Bovijn C, Lievens S, Beyaert R, Tavernier J, Peelman F. Caspase-1 targets the TLR adaptor Mal at a crucial TIR-domain interaction site. JOURNAL OF CELL SCIENCE. 2010;123(2):256–65.
IEEE
[1]
P. Ulrichts, C. Bovijn, S. Lievens, R. Beyaert, J. Tavernier, and F. Peelman, “Caspase-1 targets the TLR adaptor Mal at a crucial TIR-domain interaction site,” JOURNAL OF CELL SCIENCE, vol. 123, no. 2, pp. 256–265, 2010.
@article{834807,
  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-kappa B. 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.}},
  author       = {{Ulrichts, Peter and Bovijn, Celia and Lievens, Sam and Beyaert, Rudi and Tavernier, Jan and Peelman, Frank}},
  issn         = {{0021-9533}},
  journal      = {{JOURNAL OF CELL SCIENCE}},
  keywords     = {{MAPPIT ANALYSIS,ACTIVATION,STRUCTURAL BASIS,CRYSTAL-STRUCTURE,INTERFERON-BETA,SIGNAL-TRANSDUCTION,NF-KAPPA-B,TOLL-LIKE RECEPTOR,MYD88,MOLECULE,Caspase-1,Mal,TLR,TIR domain}},
  language     = {{eng}},
  number       = {{2}},
  pages        = {{256--265}},
  title        = {{Caspase-1 targets the TLR adaptor Mal at a crucial TIR-domain interaction site}},
  url          = {{http://dx.doi.org/10.1242/jcs.056002}},
  volume       = {{123}},
  year         = {{2010}},
}

Altmetric
View in Altmetric
Web of Science
Times cited: