STIM1 at the plasma membrane: A novel Molecular regulator of B cell migration.

Abstract

Cell migration is a fundamental process required for effective immune responses, relying on both amoeboid movement and chemotaxis. Among chemotactic pathways, the CXCL12/CXCR4 axis plays a pivotal role in guiding B cell migration. While essential under physiological conditions, this pathway is frequently dysregulated in pathological contexts such as Chronic Lymphocytic Leukemia (CLL) and Systemic Lupus Erythematosus (SLE), where altered CXCR4 expression enhances B cell retention, survival, and tissue infiltration. Calcium signaling is central to B cell migration, notably through Store-Operated Calcium Entry (SOCE), STIM1 located at the endoplasmic reticulum (ER) membrane and Orai1 calcium channels. Although STIM1 is traditionally studied as an ER protein regulating SOCE, early findings and recent work from our group indicate that STIM1 is also present at the plasma membrane (STIM1PM), where it displays a dual topology and contributes to constitutive calcium entry (CCE). The function of STIM1PM pool in B cell migration remains unknown. Here, we demonstrate that both STIM1ER and Orai1 are required for CXCL12-induced migration of B cells. Importantly, we provide the first evidence that STIM1PM, exhibiting N?terminal and C?terminal orientations, actively regulates B cell migration independently of SOCE. We show that STIM1PM controls CCE and modulates intercellular interactions, thereby influencing chemotactic responses. Targeting STIM1PM domains significantly impairs B cell migration, highlighting its potential as a novel therapeutic target in diseases characterized by aberrant B cell trafficking. Our findings uncover an unanticipated role for STIM1PM and open new perspectives on calcium?dependent and calcium?independent mechanisms of B cell migration.