title: Natural loss-of-function mutation of myeloid differentiation protein 88 disrupts its ability to form Myddosomes.
abstract: 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.
authors.affiliation: Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
authors.forename: Kamalpreet
authors.initials: K
authors.lastname: Nagpal
authors.forename: Theo S
authors.initials: TS
authors.lastname: Plantinga
authors.forename: Cherilyn M
authors.initials: CM
authors.lastname: Sirois
authors.forename: Brian G
authors.initials: BG
authors.lastname: Monks
authors.forename: Eicke
authors.initials: E
authors.lastname: Latz
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
authors.forename: Douglas T
authors.initials: DT
authors.lastname: Golenbock
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D020125:Mutation, Missense; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism
chemical_list: C507779:MYD88 protein, human; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D051193:Toll-Like Receptors