Chemokine-mediated F-actin dynamics, polarity, and migration in B lymphocytes depend on WNK1 signaling

• Published in: Science signaling Vol. 17; no. 851; p. eade1119
• Main Authors: Hwang, Il-Young, Kim, Ji Sung, Harrison, Kathleen A, Park, Chung, Shi, Chong Shan, Kehrl, John H
• Format: Journal Article
• Language: English
• Published: United States 27.08.2024
• Subjects: Actins - metabolism; Animals; B-Lymphocytes - cytology; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; Cell Movement; Cell Polarity; Chemokine CXCL13 - genetics; Chemokine CXCL13 - metabolism; GTPase-Activating Proteins; Guanine Nucleotide Exchange Factors; Mice; Mice, Inbred C57BL; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Receptors, CXCR5; Signal Transduction; WNK Lysine-Deficient Protein Kinase 1 - genetics; WNK Lysine-Deficient Protein Kinase 1 - metabolism
• ISSN: 1937-9145
• DOI: 10.1126/scisignal.ade1119

Ligand-engaged chemokine receptors trigger nucleotide exchange in heterotrimeric Gα 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 Gα 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 , 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.