Disruption of membrane cholesterol stimulates MyD88-dependent NF-kappaB activation in immature B cells.
Agents that extract or sequester membrane cholesterol stimulate IkappaB degradation and lead to NF-kappaB activation in a subset of B cells. Although the extraction of cholesterol by methyl-beta-cyclodextrin is the most potent stimulus of NF-kappaB, other agents that sequester cholesterol have similar effects. B cells and B cell lines with an immature phenotype are significantly more sensitive to the effects of cholesterol perturbation than their mature B cell counterparts. NF-kappaB activation does not involve signaling from the B cell receptor complex. Instead, the disruption of membrane cholesterol activates NF-kappaB through a MyD88-dependent pathway involving the pattern recognition receptor, Toll-like receptor 4. We suggest that lipid raft microdomains may serve not only to orchestrate receptor signaling, but to sequester signaling components one from one another, which serves to prevent receptor-mediated signaling from occurring. A role for this process during B cell development is suggested.
Department of Microbiology, Boston University School of Medicine, Boston, MA 02118, USA.
Jennifer A
JA
Flemming
Kristin H
KH
Perkins
Lia
L
Luus
Andrew R
AR
Ferguson
Ronald B
RB
Corley
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism*; D001402:B-Lymphocytes / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D021962:Membrane Microdomains / Q000378:metabolism; D051379:Mice; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism*; D051193:Toll-Like Receptors
D048868:Adaptor Proteins, Signal Transducing; D000943:Antigens, Differentiation; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D051193:Toll-Like Receptors; D002784:Cholesterol