Tyrosine phosphorylation-independent regulation of lipopolysaccharide-mediated response by the transmembrane adaptor protein LAB.
Linker for activation of B cells (LAB)/non-T cell activation linker is a transmembrane adaptor protein that functions in immunoreceptor-mediated signaling. Published studies have shown that LAB has both positive and negative roles in regulating TCR and high-affinity Fc receptor-mediated signaling and cellular function. In this study, we showed that LAB was also expressed in dendritic cells and that LAB deficiency affected LPS-mediated signaling and cytokine production. LPS-mediated MAPK activation was enhanced in LAB(-/-) bone marrow-derived dendritic cells. These bone marrow-derived dendritic cells also produced more TNF-α, IL-6, and IL-10 than wild-type cells. Moreover, LAB(-/-) mice were hyperresponsive to LPS-induced septic shock. These data indicated that LAB has a negative role in LPS-mediated responses. By using LAB knockin mice, which harbor mutations at five membrane-distal tyrosines, we further showed that, in contrast to its role in immunoreceptor-mediated signaling, LAB function in LPS-mediated signaling pathway did not depend on its tyrosine phosphorylation. Our study suggested a novel mechanism by which LAB functions in the regulation of innate immunity.
Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA.
Minghua
M
Zhu
Deirdre M
DM
Fuller
Chih-wen
CW
Ou-Yang
Sarah A
SA
Sullivan
Weiguo
W
Zhang
D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000276:immunology; D002469:Cell Separation; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D005434:Flow Cytometry; D055879:Gene Knock-In Techniques; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology*; D047468:Immunoprecipitation; D008070:Lipopolysaccharides / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D014443:Tyrosine / Q000378:metabolism
D033942:Adaptor Proteins, Vesicular Transport; D016207:Cytokines; C471359:LAB protein, mouse; D008070:Lipopolysaccharides; D014443:Tyrosine