The influence of CD40 on the association of the B cell antigen receptor with lipid rafts in mature and immature cells

Malapati, Sunil; Pierce, Susan K.

doi:10.1002/1521-4141(200112)31:12<3789::aid-immu3789>3.0.co;2-v

Cited by 17 publications

(9 citation statements)

References 36 publications

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“…32 This was different from other findings which show constitutive residence of CD40 in lipid rafts 19 or even outside of raft microdomains. 33 Moreover, cholesterol depletion by MCD did not alter the distribution or translocation pattern of CD40 in the lipid-ordered phase after CD40 engagement (Figure 4). This method was validated by the observation that Lyn, a protein that constitutively resides in lipid rafts, 34 and cytoplasmic Erk separated well in Brij58-insoluble and -soluble phases, respectively (Figure 4).…”

Section: Cholesterol-dependent and -Independent Signaling By Cd40mentioning

confidence: 91%

Cholesterol-Dependent and -Independent CD40 Internalization and Signaling Activation in Cardiovascular Endothelial Cells

Chen

Wang

et al. 2007

ATVB

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Objective-It remains elusive how CD40 endocytosis or clustering on the cell surface is induced by different forms of CD40 agonist. This study aims to investigate whether lipid rafts differentially regulate CD40 traffic and signaling in proinflammatory activation of cardiovascular endothelial cells (ECs). Methods and Results-Using fluorescent microscopy and flow cytometry, we demonstrated that soluble CD40L and agonistic antibody G28.5 induced CD40 internalization via clathrin-independent pathway. Furthermore, depletion of cholesterol by methyl-␤-cyclodextrin (MCD) or siRNA knockdown of caveolin-1 efficiently blocked CD40 internalization, suggesting that caveolae-rafts pathway regulates CD40 internalization. In contrast, a membrane-bound CD40L mimic (megamer) triggered aggregation of CD40 rafts outside of the conventional cholera toxin B subunit-positive lipid rafts resistant to cholesterol depletion. Finally, both G28.5 and megamer induced CD40 translocation to Brij58-insoluble, low buoyant density rafts, a movement insensitive to cholesterol depletion. However, MCD effectively inhibited G28.5 but not megamer-induced CD40 activation, and such inhibition could be alleviated by cholesterol reconstitution, suggesting that 2 different raft structures of CD40 induced by G28.5 or megamer possess differential sensitivity to cellular cholesterol levels in downstream signaling. Key Words: CD 40 Ⅲ lipid rafts Ⅲ endocytosis Ⅲ cholesterol Ⅲ endothelial cells C D40 is constitutively expressed on professional antigen presenting cells (APCs) 1,2 as well as nonprofessional APCs, such as endothelial cells (ECs). 3 Overactivation of CD40 in these cells leads to elevated expression of proinflammatory cytokines and adhesion molecules in chronic inflammatory diseases such as rheumatoid arthritis, graft-versus-host disease, and atherosclerosis. 2,4,5 Besides cell surface expression, CD40L can also exist in a soluble biologically active form (sCD40L) that is shed from activated T-cells 6 or stimulated platelets, 7,8 the latter accounting for 95% of circulating sCD40L. 9 Therefore, it is generally speculated that increased plasma sCD40L levels attributable to abnormal platelet activation most likely plays a role in vascular endothelial inflammation and atherogenesis. 10 Many receptors are rapidly endocytosed after ligand-induced activation and subsequently move through a series of endosomal compartments. There are 2 major pathways involved in receptor internalization depending on the different plasma membrane moiety engaged. One is the classic clathrin-mediated endocytic pathway, and the other is lipid raft-dependent route either caveolae-dependent 11 or caveolae-independent. 12 Lipid rafts are Ϸ50 to 100-nm-diameter membrane microdomains that are enriched in cholesterol and glycosphingolipids 13 and invisible under any optical microscopes. 14,15 They serve as an important platform for bringing related signaling proteins together to initiate specific signal pathway. 16 Many important signaling proteins, including glycosylphosphatid...

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Section: Cholesterol-dependent and -Independent Signaling By Cd40mentioning

confidence: 91%

Cholesterol-Dependent and -Independent CD40 Internalization and Signaling Activation in Cardiovascular Endothelial Cells

Chen

Wang

et al. 2007

ATVB

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“…Thus, in naive mature B cells, the BCR complex is excluded from rafts in order to maintain the BCR in its' resting state. Antigen binding enables the BCR to enter lipid rafts and propagate signals downstream of the BCR [120,121]. The translocation of the BCR into rafts is usually a transient process but it can be prolonged by the activation of co-receptors including CD19/CD21 [119] providing a rationale for the ability of such co-receptors to reduce the threshold of BCR activation.…”

Section: Influence Of Lipid Rafts On Functional Outcomementioning

confidence: 99%

Differential signalling during B-cell maturation

2005

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“…35 To clarify this point, our flotation assay was modified to allow preparation of the rafts in more "physiological" conditions: cell homogenates were prepared at 37°C by mechanical disruption only, in the absence of any detergents, and subsequently fractionated on a discontinuous gradient as usual. We found this procedure to be applicable to several cell types including Bjab cells; the rafts obtained using this modified assay were called "detergent-free" rafts.…”

Section: Cd40 Activation Induces a Redistribution Of Traf2 And Traf3 mentioning

confidence: 99%

TRAF interactions with raft‐like buoyant complexes, better than TRAF rates of degradation, differentiate signaling by CD40 and EBV latent membrane protein 1

Ardila-Osorio

Pioche−Durieu

Puvion‐Dutilleul

et al. 2004

Intl Journal of Cancer

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The CD40 receptor and the Epstein-Barr virus oncoprotein LMP1 are both members of the TNF-receptor family and share several signaling mediators, including TRAF2 and TRAF3. Depending on the cell lineage and stage of maturation, LMP1 and CD40 can have synergistic, antagonist or unrelated effects. Previous publications have suggested that both TRAF2 and TRAF3 move into lipid rafts upon LMP1 expression or CD40 activation, whereas their proteolysis is only enhanced by CD40. However CD40-induced proteolysis of TRAF2 has only been reported in murine cells, and there are conflicting data regarding translocation of TRAF2 into lipid rafts. We therefore investigated TRAF2 and TRAF3 modifications induced by CD40 and LMP1 signaling in a panel of human cell lines of lymphoid and epithelial origins. Upon CD40 stimulation, a marked redistribution of TRAF2 into the buoyant raft fraction was observed in all cell lines and was often associated with a similar redistribution of TRAF3. In contrast, only TRAF3 was redistributed into the raft fraction upon LMP1 expression. Moreover parallel changes in subcellular distribution of TRAF2 and TRAF3 were recorded by electron microscopy. A significant decrease in TRAF2 and TRAF3 concentrations triggered by CD40 ligation was observed in only 1 cell line and there was no evidence that this decrease was required for the negative feed-back on JNK activation. TRAF2 redistribution into raft-like complexes thus appears as the most significant event distinctive of CD40 and LMP1 signaling. On the other hand, the parallel influence of CD40 and LMP1 on TRAF3 redistribution is consistent with functional similarities between the CD40-TRAF3 and LMP1-TRAF3 axes.Key words: TRAF2; TRAF3; CD40; raft; EBV; LMP1 CD40 is a membrane receptor of the TNF-receptor family, which is a key effector of B-lymphocyte maturation and immune cell cooperation. It is also involved in the homeostasy of nonimmune cell types, especially epithelial and endothelial cells. 1,2 Latent Membrane Protein 1 (LMP1) is the main Epstein-Barr virus (EBV) oncogenic protein. It is consistently expressed in several human EBV-associated malignancies of lymphoid and epithelial origin. 3,4 LMP1 and CD40 share a series of common signaling mediators including TRAF2, TRAF3, TRAF5 and TRAF6. 5-8 A large number of signaling pathways can be activated by both membrane proteins including the NF-kB, JNK/AP1, p38/MAPK and PI3-Kinase pathways. 2,8,9,10 Numerous reports have emphasized the fact that LMP1 can mimic a constitutively active CD40-like receptor, although it does not have extracellular ligand. For example LMP1 and CD40 signals are interchangeable in supporting proliferation of human B-cells transformed with a "mini-EBV" system. 11 Both LMP1 and overexpressed CD40 can enhance EGF-receptor expression in epithelial cells. 5 Moreover, in a peculiar experimental context, LMP1 can mimic the Ig class switching activity of CD40. 12 However, LMP1 and activated CD40 have not only convergent but also distinct or even antagonistic effects. 13,14 CD40 contribut...

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The influence of CD40 on the association of the B cell antigen receptor with lipid rafts in mature and immature cells

Cited by 17 publications

References 36 publications

Cholesterol-Dependent and -Independent CD40 Internalization and Signaling Activation in Cardiovascular Endothelial Cells

Cholesterol-Dependent and -Independent CD40 Internalization and Signaling Activation in Cardiovascular Endothelial Cells

Differential signalling during B-cell maturation

TRAF interactions with raft‐like buoyant complexes, better than TRAF rates of degradation, differentiate signaling by CD40 and EBV latent membrane protein 1

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