LRBA regulates actin cytoskeleton dynamics through NMIIA during B cell immune responses.

Patients with lipopolysaccharide-responsive beige-like anchor protein (LRBA) deficiency typically suffer from severe B cell dysfunction. However, the underlying mechanisms remain incompletely understood. In this study, we identify non-muscle myosin IIA (NMIIA) as an interaction partner of LRBA in B cells, and uncover a role for LRBA in regulating actin cytoskeleton dynamics during B cell activation. LRBA-deficient B cells exhibit abnormal migration, impaired F-actin polymerization, and reduced B cell receptor signalling and polarization upon activation. In addition, LRBA deficiency severely disrupts immune synapse formation as evidenced by diminished central SMAC formation, reduced microtubule organizing center translocation and disrupted BCR and lysosome polarization. Consistent with these defects, internalization of the BCR-antigen complex is also impaired. Mechanistically, NMIIA activation, assessed by myosin light chain (MLC) phosphorylation, is reduced in LRBA-deficient cells. In addition, LRBA co-localizes with active NMIIA during both migration and immune synapse formation. Collectively, our findings establish LRBA as an important regulator of cytoskeleton dynamics during B cell activation, which may contribute to the defective humoral immunity observed in LRBA-deficient patients.