| Autor: |
Hwang, Il-Young, Kim, Ji Sung, Harrison, Kathleen A., Park, Chung, Shi, Chong Shan, Kehrl, John H. |
| Předmět: |
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| Zdroj: |
Science Signaling; 8/27/2024, Vol. 17 Issue 851, p1-18, 18p |
| Abstrakt: |
Ligand-engaged chemokine receptors trigger nucleotide exchange in heterotrimeric Gαi proteins, which stimulates cytoskeletal reorganization and cell polarity changes. To better understand the signaling events responsible for these cellular changes, we focused on early changes in F-actin dynamics after engagement of the chemokine receptor CXCR5 in murine splenic B cells. Within 10 seconds of exposure to the CXCR5 ligand CXCL13, three-dimensional lamellar-like pseudopods and F-actin–rich ridges appeared. The transient F-actin increase depended on Gαi2/3 signaling, the PI3K/AKT pathway, ERK activation, phospholipase C activity, and Rac1/2 activation mediated by Dock2 (dedicator of cytokinesis 2). Immunoblot analyses identified the kinase WNK1 (with no lysine kinase 1) as a potential early AKT effector. Treating B cells with specific WNK inhibitors disrupted F-actin dynamics and impaired B cell polarity, motility, and chemotaxis. These changes were mimicked in a murine B cell line by CRISPR-Cas9 gene editing of Wnk1, which also suggested that WNK1 contributed to B cell proliferation. Administration of a single dose of a WNK inhibitor transiently reduced B cell motility and polarity in the lymph nodes of live mice. These results indicate that WNK1 signaling maintains B cell responsiveness to CXCL13 and suggest that pharmacological inhibition of WNK1, which is involved in cancer progression and blood pressure regulation, may affect humoral immunity. Editor's summary: The chemokine CXCL13 induces cytoskeletal changes that enable B cells to migrate to sites of inflammation. Hwang et al. identified the activation of the kinase WNK1 as an early signaling event triggered by CXCL13 in B cells. Pharmacological inhibition or genetic deletion of WNK1 prevented CXCL13-induced cytoskeletal changes and migration in primary mouse B cells and B cell lines. Pharmacological inhibition of WNK1 also reduced B cell motility in mouse lymph nodes. Thus, suppressing B cell responses to CXCL13 could be a side effect of inhibiting WNK1, which is a potential therapeutic target in cancer and hypertension. —Wei Wong [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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