Lipopolysaccharide-responsive beige-like anchor (LRBA), a novel regulator of human immune disorders

Lipopolysaccharide (LPS)-responsive beige-like anchor (LRBA) is a novel gene essential for the normal function of the immune system. It is the eighth common variable immunodeficiency (CVID) gene, mutation of which causes CVID and autoimmunity, and is associated with inflammation. LRBA is a unique CVID gene when compared to other CVID genes: it is a large, PKA anchor and vesicle trafficking regulator. Other seven CVID genes that are associated with CVID are cell receptors. However, the molecular mechanism by which LRBA regulates the immune system is unknown. LRBA protein contains Concanavalin A (ConA)-like lectin binding domain, Vacuolar protein sorting-27, hepatocyte growth factor-regulated tyrosine kinase substrate domain and signal transducing adaptor molecule (VHS) domain, two RII binding motifs, WD-like (WDL), and Beige and Chediak-Higashi (BEACH) domains and five WD40 repeats (WBW super domain). An LC3 interaction region (LIR), which is involved in autophagy, is also predicted in LRBA. The WBW super domain defined the WBW gene family, members of which appear to function as scaffolding proteins in vesicle trafficking and are important in human diseases. The cargo proteins regulated by LRBA through vesicle trafficking may include cytokines and antibodies for secretion, plasma membrane proteins for disposition on the membrane, and proteins trafficking between different membrane compartments, or proteins for degradation through lysosome/autophagy or proteasome degradation. Specifically, LRBA interacts with multiple important signal transduction pathways, including epidermal growth factor receptor (EGFR), Notch, PKA, Ras, E2F1, p53, and mitogen-activated protein kinases (MAPKs). These molecular interactions may help to understand why and how LRBA is involved in critical cellular processes such as cell proliferation, apoptosis and autophagy, and plays a fundamental role in the normal immune system.