Journal
JOURNAL OF IMMUNOLOGY
Volume 185, Issue 6, Pages 3391-3400Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.0903147
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Funding
- National Basic Research Program (973) [2007CB815800]
- State High-Tech Development Project (863) [2006AA09Z433, 2008AA092603]
- Ministry of Science and Technology of China [2007DFA30840]
- Ministry of Education [0107]
- Commission of Science and Technology of Guangdong Province , Guangzhou City
- Sun Yat-Sen University Science Foundation
- National Natural Science Foundation of China [30730089]
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MyD88 and Toll/IL-1R domain-containing adaptor protein (TIRAP) are required for the TLR4 response to LPS stimulation in mammals, but the functions of the two adaptors and their involvement in zebrafish insensitivity to LPS remains unknown. We present a functional analysis of zebrafish Myd88 and Tirap and suggest that Myd88 is more important than Tirap for the activation of Tlr-mediated NF-kappa B, which may be a novel mechanism of Myd88-dependent TLR signaling in teleosts. Zebrafish Tirap lacks the phosphatidylinositol 4,5-bisphosphate binding motif required for human TIRAP location and has leucine at position 233 rather than the conserved proline of human TIRAP, as well as 105 additional aa at the N terminus. Overexpression of zebrafish Tirap in HEK293T cells did not activate NF-kappa B and IFN-beta, but slightly activated NF-kappa B in carp leukocyte cells. Zebrafish Myd88 alone strongly induced the activation of NF-kappa B and IFN-beta both in HEK293T and carp leukocyte cells. The function of Myd88 was dependent on its cellular location and the proline in the Toll/IL-1R domain. Although zebrafish Tirap was distributed throughout the cell rather than localized to the cytoplasmic membrane, its impaired ability to activate downstream Tlr molecules was unlikely to be related to its location because chimera TIRAP with a human TIRAP N terminus and membrane-binding domain also did not activate NF-kappa B. However, the mutation of leucine to proline increased the ability of Tirap to activate NF-kappa B. We suggest that the zebrafish Tirap needs a longer N terminus to perform its function and could be partially responsible for the resistance to LPS in zebrafish. The Journal of Immunology, 2010, 185: 3391-3400.
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