The inositol 5-phosphatase INPP5B regulates B cell receptor clustering and signaling

Alaa Droubi, Connor Wallis, Karen E Anderson, Saifur Rahman, Aloka de Sa, Taufiq Rahman, Len R Stephens, Philip T Hawkins, Martin Lowe

Research output: Contribution to journalArticlepeer-review

Abstract

Upon antigen binding, the B cell receptor (BCR) undergoes clustering to form a signalosome that propagates downstream signaling required for normal B cell development and physiology. BCR clustering is dependent on remodeling of the cortical actin network, but the mechanisms that regulate actin remodeling in this context remain poorly defined. In this study, we identify the inositol 5-phosphatase INPP5B as a key regulator of actin remodeling, BCR clustering, and downstream signaling in antigen-stimulated B cells. INPP5B acts via dephosphorylation of the inositol lipid PI(4,5)P2 that in turn is necessary for actin disassembly, BCR mobilization, and cell spreading on immobilized surface antigen. These effects can be explained by increased actin severing by cofilin and loss of actin linking to the plasma membrane by ezrin, both of which are sensitive to INPP5B-dependent PI(4,5)P2 hydrolysis. INPP5B is therefore a new player in BCR signaling and may represent an attractive target for treatment of B cell malignancies caused by aberrant BCR signaling.

Original languageEnglish
Article numbere202112018
JournalThe Journal of cell biology
Volume221
Issue number9
DOIs
Publication statusPublished - 5 Sept 2022

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