LRRC8A
This gene encodes a protein belonging to the leucine-rich repeat family of proteins, which are involved in diverse biological processes, including cell adhesion, cellular trafficking, and hormone-receptor interactions. This family member is a putative four-pass transmembrane protein that plays a role in B cell development. Defects in this gene cause autosomal dominant non-Bruton type agammaglobulinemia, an immunodeficiency disease resulting from defects in B cell maturation. Multiple alternatively spliced transcript variants, which encode the same protein, have been identified for this gene. [provided by RefSeq]
Full Name
leucine rich repeat containing 8 family, member A
Function
Essential component of the volume-regulated anion channel (VRAC, also named VSOAC channel), an anion channel required to maintain a constant cell volume in response to extracellular or intracellular osmotic changes (PubMed:24725410, PubMed:29769723, PubMed:24790029, PubMed:26530471, PubMed:26824658, PubMed:28193731).
The VRAC channel conducts iodide better than chloride and can also conduct organic osmolytes like taurine (PubMed:24725410, PubMed:30095067, PubMed:24790029, PubMed:26530471, PubMed:26824658, PubMed:28193731).
Mediates efflux of amino acids, such as aspartate and glutamate, in response to osmotic stress (PubMed:28193731).
LRRC8A and LRRC8D are required for the uptake of the drug cisplatin (PubMed:26530471).
In complex with LRRC8C or LRRC8E, acts as a transporter of immunoreactive cyclic dinucleotide GMP-AMP (2'-3'-cGAMP), an immune messenger produced in response to DNA virus in the cytosol: mediates both import and export of 2'-3'-cGAMP, thereby promoting transfer of 2'-3'-cGAMP to bystander cells (PubMed:33171122).
In contrast, complexes containing LRRC8D inhibit transport of 2'-3'-cGAMP (PubMed:33171122).
Required for in vivo channel activity, together with at least one other family member (LRRC8B, LRRC8C, LRRC8D or LRRC8E); channel characteristics depend on the precise subunit composition (PubMed:24790029, PubMed:26824658, PubMed:28193731).
Can form functional channels by itself (in vitro) (PubMed:26824658).
Involved in B-cell development: required for the pro-B cell to pre-B cell transition (PubMed:14660746).
Also required for T-cell development (By similarity).
Required for myoblast differentiation: VRAC activity promotes membrane hyperpolarization and regulates insulin-stimulated glucose metabolism and oxygen consumption (By similarity).
Also acts as a regulator of glucose-sensing in pancreatic beta cells: VRAC currents, generated in response to hypotonicity- or glucose-induced beta cell swelling, depolarize cells, thereby causing electrical excitation, leading to increase glucose sensitivity and insulin secretion (PubMed:29371604).
Also plays a role in lysosome homeostasis by forming functional lysosomal VRAC channels in response to low cytoplasmic ionic strength condition: lysosomal VRAC channels are necessary for the formation of large lysosome-derived vacuoles, which store and then expel excess water to maintain cytosolic water homeostasis (PubMed:31270356, PubMed:33139539).
Biological Process
Anion transmembrane transportManual Assertion Based On ExperimentIDA:UniProtKB
Anion transportManual Assertion Based On ExperimentIMP:UniProtKB
Aspartate transmembrane transportIEA:Ensembl
Cell volume homeostasisManual Assertion Based On ExperimentIDA:UniProtKB
Cellular glucose homeostasisISS:UniProtKB
Chloride transmembrane transportManual Assertion Based On ExperimentIDA:UniProtKB
Cyclic-GMP-AMP transmembrane import across plasma membraneManual Assertion Based On ExperimentIDA:UniProtKB
Positive regulation of insulin secretionISS:UniProtKB
Positive regulation of myoblast differentiationISS:UniProtKB
Pre-B cell differentiationISS:UniProtKB
Protein hexamerizationManual Assertion Based On ExperimentIDA:UniProtKB
Response to osmotic stressManual Assertion Based On ExperimentIMP:UniProtKB
SpermatogenesisISS:UniProtKB
Taurine transportIEA:Ensembl
Cellular Location
Cell membrane
Lysosome membrane
Mainly localizes to the cell membrane, with some intracellular localization to lysosomes.
Involvement in disease
Agammaglobulinemia 5, autosomal dominant (AGM5):
A primary immunodeficiency characterized by profoundly low or absent serum antibodies and low or absent circulating B-cells due to an early block of B-cell development. Affected individuals develop severe infections in the first years of life.
Topology
Cytoplasmic: 1-23
Helical: 24-47
Extracellular: 48-123
Helical: 124-142
Cytoplasmic: 143-264
Helical: 265-286
Extracellular: 287-316
Helical: 317-341
Cytoplasmic: 342-810