Structure and Function of the LRBA Protein

Review Beige and Chediak (BEACH) Domaincontaining Protein (BDCP) Family ProteinsLRBA, the main focus of this review article, is a large 319 kDa protein with pleiotropic function.Patients with LRBA deficiency present with common variable immunodeficiency with a predominant regulatory T-cell defect (1,2).The phenotypes of this disease are very similar to CTLA4 deficiency and point to the fact that LRBA is responsible for CTLA4 surface expression on regulatory T lymphocytes (3-5).LRBA knockout mice also display very similar phenotypes to patients, although LRBA dependent CTLA4 deficiency does not proceed to full-blown immune dysregulation in this case (6).LRBA belongs to a family of 9 proteins, all containing a Beach domain, encoded by the human genome with similar domain structures (Figure 1) ( 7).An alignment of the amino acid sequences of the family members demonstrates a high level of conservation in key residues (Figure 2).Several of these PH-Beach proteins were implicated in human disease.LYST (lysosomal trafficking regulator) is mutated in Chédiak-Higashi syndrome (CHS), an autosomal recessive disease that has a lysosomal phenotype and results in hypopigmentation, abnormal bleeding and increased susceptibility to infection with defects in the nervous system (8).Mutations in the murine Lyst gene cause coat color phenotypes consistent with the human disease and in the lysosomal trafficking role for this protein (9,10).In fact, CHS patients' T-cells, similar to LRBA deficiency, do not express appropriate levels of CTLA4, indicating that some redundancy may be at play among LRBA, LYST and also NBEAL2 (11).NBEAL2 (Neurobeachin-like protein 2) mutations cause Gray Platelet syndrome (GPS), with abnormalities in the biogenesis of thrombocytes and their secretory α-granules (12).Reduced Neurobeachin (Nbea/ Lyst2) expression, a neuronal membrane trafficking protein controlling neuronal feeding circuits, was associated with obesity in mice and humans (13).All of these phenotypes point to the lysosomal functions of this family of proteins.