MyD88: central relay station of Interleukin 1 signaling pathway.
Degree: PhD, Microbiology and Immunology, 2005, Vanderbilt University
As inflammation is a major mechanism of disease, we investigated the signal transduction processes induced by the key inflammatory cytokine Interleukin (IL) 1 beta as well as the genome responses to pathogen-derived proinflammatory agonists. Myeloid differentiation primary response gene (MyD88) is the essential adaptor protein that transduces intracellular signals generated by the IL-1Ã¢ receptor and multiple Toll-like receptors (TLRs) that recognize diverse pathogen surfaces. The IL-1Ã¢ receptor complex interacts with MyD88 via the Toll/IL-1 receptor (TIR) domain. Here we identified the MyD88 TIR domain binding sites involved in IL-1Ã¢-induced protein-protein interactions. The MyD88 TIR domain required Box3 to act as dominant negative inhibitor of IL-1Ã¢ signaling. Accordingly, mutations of residues 285-286 reversed the dominant negative effect of the MyD88 TIR domain on NFÃªB-dependent reporter gene activity and IL-6 production. Moreover, mutations of residues 171 in helix Ã¡A, 195-197 in Box2, and 275 in the Ã¢E strand had similar functional effects. Strikingly, mutations of residues 195-197 eliminated the TIR-TIR interaction of MyD88 and IL-1 receptor accessory protein (IL1RAcP). Mutations in Box2 and 3 prevented homotypic MyD88 oligomerization via the TIR domain. Overall, structure-function analysis produced a 3-dimensional docking model of TIR-TIR interaction between MyD88 and IL1RAcP.
Animal models of systemic inflammation induced by staphylococcal enterotoxin B (SEB) and lipopolysaccharide (LPS) were used to study genome-wide transcriptional response. In vivo treatment with SEB induced 134 and 209 genes in spleen cells and T lymphocytes, respectively. Upregulation of these genes was inhibited by blocking NFÃªB signaling with a cell-penetrating nuclear import inhibitor cSN50 peptide or the IÃªBÃ¡ÃN transgene. In vivo treatment of LPS induced upregulation of 1296 genes and downregulation of 1551 genes in the liver and correspondingly, 1109 and 402 genes in the spleen. The genome-wide response to LPS was ablated in TLR-4-deficent C3H/HeJ mice. The cSN50 peptide blocked 547 LPS-inducible and 669 LPS-downregulated genes in the liver, and 105 LPS-inducible and 230 LPS-suppressed genes in the spleen. Thus, nuclear import of NFÃªB and other stress-responsive transcription factors plays an important role in genome-wide response to microbial inducers of inflammation.
Advisors/Committee Members: Derya Unutmaz (chair), Jack J Hawiger (committee member), Brian E Wadzinski (committee member), Dean W. Ballard (committee member), Luc Van Kaer (committee member).
Subjects/Keywords: IL-1beta signaling pathway; MyD88; gene expression profiling; inflammation; nuclear import; IL-1 receptor accessary protein; Interleukin-1; Cellular signal transduction
to Zotero / EndNote / Reference
APA (6th Edition):
Li, C. (2005). MyD88: central relay station of Interleukin 1 signaling pathway. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://etd.library.vanderbilt.edu/available/etd-12132005-122759/ ;
Chicago Manual of Style (16th Edition):
Li, Chunsheng. “MyD88: central relay station of Interleukin 1 signaling pathway.” 2005. Doctoral Dissertation, Vanderbilt University. Accessed October 16, 2019.
MLA Handbook (7th Edition):
Li, Chunsheng. “MyD88: central relay station of Interleukin 1 signaling pathway.” 2005. Web. 16 Oct 2019.
Li C. MyD88: central relay station of Interleukin 1 signaling pathway. [Internet] [Doctoral dissertation]. Vanderbilt University; 2005. [cited 2019 Oct 16].
Available from: http://etd.library.vanderbilt.edu/available/etd-12132005-122759/ ;.
Council of Science Editors:
Li C. MyD88: central relay station of Interleukin 1 signaling pathway. [Doctoral Dissertation]. Vanderbilt University; 2005. Available from: http://etd.library.vanderbilt.edu/available/etd-12132005-122759/ ;