SHEP1 partners with CasL to promote marginal zone B-cell maturation
Cecille D Browne1, Melanie M Hoefer, Suresh K Chintalapati
1Infectious and Inflammatory Disease Center, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
Insights
The adaptor protein SHEP1 is crucial for marginal zone B-cell maturation and retention in the spleen. It works with CasL, mediating signals from B-cell receptors and S1P receptors to control B-cell movement.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- The spleen's marginal zone is a critical immune niche for B cells and macrophages, capturing bloodborne antigens.
- Integrin-mediated signaling, influenced by G protein-coupled receptors (GPCRs) and B-cell receptors (BCR), retains marginal zone B cells.
- Sphingosine-1-phosphate (S1P) signaling is vital for B-cell localization in the marginal zone, but downstream pathways remain unclear.
Purpose of the Study:
- To investigate the role of the adaptor protein SHEP1 in marginal zone B-cell maturation and function.
- To elucidate the downstream signaling mechanisms linking BCR and S1P receptors to B-cell retention in the marginal zone.
Main Methods:
- Investigated the requirement of SHEP1 for marginal zone B-cell maturation.
- Examined the association between SHEP1 and the scaffolding protein CasL in B cells.
- Assessed the impact of SHEP1 on CasL phosphorylation induced by BCR or S1P receptors.
Main Results:
- SHEP1 is essential for the maturation of marginal zone B cells.
- SHEP1 and CasL form a constitutive complex within B cells.
- SHEP1 facilitates the hyperphosphorylation of CasL, a process critical for lymphocyte adhesion and motility, upon activation of BCR or S1P receptors.
Conclusions:
- SHEP1 acts as a key downstream effector for both BCR and S1P receptors in marginal zone B cells.
- SHEP1 orchestrates B-cell movement and retention within the spleen's marginal zone by modulating CasL phosphorylation.
Abstract:
The marginal zone is a cellular niche bordering the marginal sinus of the spleen that contains specialized B-cell and macrophage subsets poised to capture bloodborne antigens. Marginal zone B cells are retained in this niche by integrin-mediated signaling induced by G protein-coupled receptors (GPCRs) and, likely, the B-cell receptor (BCR). Sphingosine-1-phosphate (S1P) signaling via the S1P family of GPCRs is known to be essential for B-cell localization in the marginal zone, but little is known about the downstream signaling events involved. Here, we demonstrate that the adaptor protein SHEP1 is required for marginal zone B-cell maturation. SHEP1 functions in concert with the scaffolding protein CasL, because we show that SHEP1 and CasL are constitutively associated in B cells. SHEP1 association is required for the BCR or S1P receptor(s) to induce the conversion of CasL into its serine/threonine hyperphosphorylated form, which is important for lymphocyte adhesion and motility. Thus, SHEP1 orchestrates marginal zone B-cell movement and retention as a key downstream effector of the BCR and S1P receptors.
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