Natural loss-of-function mutation of myeloid differentiation protein 88 disrupts its ability to form Myddosomes
Publication year
2011Source
Journal of Biological Chemistry, 286, 13, (2011), pp. 11875-82ISSN
Publication type
Article / Letter to editor
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Organization
Internal Medicine
Journal title
Journal of Biological Chemistry
Volume
vol. 286
Issue
iss. 13
Page start
p. 11875
Page end
p. 82
Subject
N4i 1: Pathogenesis and modulation of inflammation NCMLS 1: Infection and autoimmunityAbstract
Myeloid differentiation protein 88 (MyD88) is a key signaling adapter in Toll-like receptor (TLR) signaling. MyD88 is also one of the most polymorphic adapter proteins. We screened the reported nonsynonymous coding mutations in MyD88 to identify variants with altered function. In reporter assays, a death domain variant, S34Y, was found to be inactive. Importantly, in reconstituted macrophage-like cell lines derived from knock-out mice, MyD88 S34Y was severely compromised in its ability to respond to all MyD88-dependent TLR ligands. Unlike wild-type MyD88, S34Y is unable to form distinct foci in the cells but is present diffused in the cytoplasm. We observed that IRAK4 co-localizes with MyD88 in these aggregates, and thus these foci appear to be "Myddosomes." The MyD88 S34Y loss-of-function mutant demonstrates how proper cellular localization of MyD88 to the Myddosome is a feature required for MyD88 function.
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- Academic publications [238430]
- Electronic publications [122512]
- Faculty of Medical Sciences [90359]
- Open Access publications [97507]
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