Abstract
BEACH domain proteins are involved in membrane protein traffic and human diseases, but their molecular mechanisms are not understood. The BEACH protein LRBA has been implicated in immune response and cell proliferation, and human LRBA mutations cause severe immune deficiency. Here, we report a first functional and molecular phenotype outside the immune system of LRBA-knockout mice: compromised olfaction, manifesting in reduced electro-olfactogram response amplitude, impaired food-finding efficiency, and smaller olfactory bulbs. LRBA is prominently expressed in olfactory and vomeronasal chemosensory neurons of wild-type mice. Olfactory impairment in the LRBA-KO is explained by markedly reduced concentrations (20–40% of wild-type levels) of all three subunits αolf, β1 and γ13 of the olfactory heterotrimeric G-protein, Golf, in the sensory cilia of olfactory neurons. In contrast, cilia morphology and the concentrations of many other proteins of olfactory cilia are not or only slightly affected. LRBA is also highly expressed in photoreceptor cells, another cell type with a specialized sensory cilium and heterotrimeric G-protein-based signalling; however, visual function appeared unimpaired by the LRBA-KO. To our knowledge, this is the first observation that a BEACH protein is required for the efficient subcellular localization of a lipid-anchored protein, and of a ciliary protein.
Highlights
Several BEACH proteins are implicated in human diseases[1]
It remains possible that proteins representing either the N-terminal 149 aa alone, or spliced in-frame to coding exons downstream of the immunogen sequence and undetectable by the antibody, remain stably expressed and exert hypomorphic or dominant-negative effects, but this seems unlikely
As NBEA and LRBA are both implicated in the subcellular distribution of membrane proteins, and a survey of multiple Lrba/gt mouse tissues by whole-mount LacZ staining indicated LRBA expression in olfactory epithelium (OE), we investigated their involvement in the functional expression of proteins of the olfactory signal transduction chain
Summary
Several BEACH proteins are implicated in human diseases[1]. LYST (lysosomal trafficking regulator) is mutated in Chédiak-Higashi syndrome and the beige mouse (the acronym BEACH is derived from “beige and Chédiak-Higashi”). LRBA was identified as a gene product which is up-regulated in stimulated immune cells and in cancer cells[4, 9] Consistent with these experimental findings, genetic LRBA deficiency causes immunological abnormalities in humans[10,11,12,13] and mice[14]. Upon closer scrutiny we found impaired olfaction by LRBA-KO mice, concurrent with reduced abundance of the heterotrimeric G-protein, Golf, in the sensory cilia of olfactory neurons. With these results, BEACH proteins continue to emerge as a novel and scarcely explored molecular principle in the orchestration of subcellular protein distribution
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