The biology of the beige-like protein LRBA in health and disease

• Applicant: Professor Dr. Bodo Grimbacher
• Subject Area: Cell Biology ; Human Genetics ; Immunology
• Term: from 2015 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 267792999

We discovered in 2012 that mutations in the gene LRBA in humans lead to an immune dysregulation syndrome (López-Herrera et al., AJHG). This disease is characterized by a chronic inflammatory bowel disease, severe autoimmunity and an increased infection susceptibility. Not much is know on the biological functions of LRBA:-LRBA is expressed ubiquitously (Wu C et al., 2009)-Its expression increases following cell activation (Wang X et al., 2000)-From co-localization studies with fluorescence microscopy we know that LRBA is located at endosomes and lysosomes (Wang JW et al., 2001)-Proteins from the same family (BEACH proteins) mediate the link between cellular vesicles and the actin cytoskeleton (Cullinane et al., 2013)-A link between BEACH proteins and autophagy is published (Rahman et al., 2012) In this project we suggest to further study the genetics and the biology of LRBA to learn about its role in the immune system and to identify possible novel targets for the treatment of inflammatory bowel disease, severe autoimmunity and infection susceptibility.In WP1 we will approach the question why the lack of an ubiquitously expressed protein leads to a phenotype limited to the immune system. We will study the expression and splice variants of LRBA and its homologs in different cell populations and following various stimuli. Moreover, we will study the gene expression profile of LRBA-deficient cells. Our preliminary data show that LRBA (320 kDa in size) forms complexes of 880 kDa. In WP2 we wish to identify interaction partners of LRBA. We propose to do this by two means: The hypothesis-driven approach, by identifying potential interaction partners by co-immunoprecipitation; and the hypothesis-free approach, by SILAC-mass spectroscopy. We will study the function of LRBA in WP3 by verifying or falsifying the following hypotheses:-LRBA is important for the chemotaxis of lymphocytes-LRBA plays a critical role in immune receptor recycling-LRBA plays a critical role in autophagy-LRBA interferes with the mTOR signaling pathwayDiscoveries on the function of genes/proteins of the human immune system, which manifest as monogenetic human disease traits, are especially interesting for translational research, as these genes/proteins define Achilles heels of the immune system, specifically relevant for therapeutic targeting.

• DFG Programme: Research Grants