A natural loss-of-function mutation of MyD88 disrupts its ability to form Myddosomes
Interdisciplinary Graduate Program
Department of Medicine, Division of Infectious Diseases and Immunology
Medical Subject Headings
Myeloid Differentiation Factor 88
Immunology and Infectious Disease | Life Sciences | Medicine and Health Sciences
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 non-synonymous 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 knockout 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 colocalizes 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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Citation: Kamalpreet Nagpal K, Plantinga TS, Sirois CM, Monks BG, Latz E, Netea MG, Golenbock DT. (2011). Natural Loss-of-function Mutation of Myeloid Differentiation Protein 88 Disrupts Its Ability to Form Myddosomes. J Biol Chem. 2011 Apr 1;286(13):11875-82. First Published on February 16, 2011, doi:10.1074/jbc.M110.199653.