Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
Annotation inferences using phylogenetic trees
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
Gene Ontology annotation based on curation of immunofluorescence data
Combined Automated Annotation using Multiple IEA Methods
Defining the membrane proteome of NK cells.
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The study generated a membrane-enriched proteomic inventory from the human NK-like YTS cell line, the context underlying the LRBA HDA membrane annotation.
"The present study was initiated to define the composition of the membrane
proteome of the Natural Killer (NK) like cell line YTS."
AUTOIMMUNE DISEASE. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy.
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LRBA colocalizes with CTLA4 in endosomal vesicles and protects CTLA4 from lysosomal degradation, maintaining CTLA4 protein in activated and regulatory T cells.
"We found that LRBA colocalized with CTLA4 in endosomal vesicles and
that LRBA deficiency or knockdown increased CTLA4 turnover, which resulted in
reduced levels of CTLA4 protein in FoxP3(+) regulatory and activated
conventional T cells. In LRBA-deficient cells, inhibition of lysosome
degradation with chloroquine prevented CTLA4 loss."
Dominant TOM1 mutation associated with combined immunodeficiency and autoimmune disease.
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Proximity proteomics found LRBA associated with TOM1 and TOLLIP in a Golgi/trans-Golgi transport context.
"LRBA interacted with both TOM1 and TOLLIP but had molecular context mainly in the Golgi/trans-Golgi transport."
ATG4 family proteins drive phagophore growth independently of the LC3/GABARAP lipidation system.
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Functional proximity-network experiments implicate LRBA in ATG9A-vesicle delivery to damaged mitochondria during PINK1/Parkin mitophagy.
"ATG4 proximity networks reveal a role for ATG4s
and their proximity partners, including the immune-disease protein LRBA, in
ATG9A vesicle trafficking to mitochondria."
Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
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BioPlex generated large, cell-line-specific human interaction networks that provide the source context for the LRBA-CTLA4 IPI record.
"Through affinity-purification
mass spectrometry, we have created two proteome-scale, cell-line-specific
interaction networks."
Multimodal cell maps as a foundation for structural and functional genomics.
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The study integrates interaction and imaging modalities into human cell maps, providing the source context for an LRBA-CTLA4 IPI record.
"Here we substantially scale the cell mapping datasets and pipeline, yielding protein biophysical interactions and protein IF images for a matched set of more than 5,100 proteins in U2OS cells (Fig. 1)."
Identification of a novel lipopolysaccharide-inducible gene with key features of both A kinase anchor proteins and chs1/beige proteins.
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The original LBA study found LPS-inducible expression, three tissue-dependent transcript isoforms, and stimulated vesicular/trans-Golgi/lysosomal localization.
"Expression of lba is induced after LPS stimulation of B cells and macrophages.
In addition, lba is expressed in many other tissues in the body and has three
distinct mRNA isoforms that are differentially expressed in various tissues.
Strikingly, LBA-green-fluorescent protein (GFP) fusion proteins are localized to
vesicles after LPS stimulation. Confocal microscopy indicates this protein is
colocalized with the trans-Golgi complex and some lysosomes."
BCL8 is a novel, evolutionarily conserved human gene family encoding proteins with presumptive protein kinase A anchoring function.
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Human LRBA maps to 4q32, is ubiquitously expressed, and is closely related to the large BCL8B protein.
"LRBA, a human gene with a ubiquitous expression pattern mapping to 4q32, encodes
a protein closely related to BCL8."
Crystal structure of the PH-BEACH domains of human LRBA/BGL.
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The human LRBA PH-BEACH tandem has an intimate domain association, while the noncanonical PH domain did not bind phospholipids in the reported assays.
"However, our binding assays demonstrate that the PH domain
in the BEACH proteins cannot bind phospholipids."
Deleterious mutations in LRBA are associated with a syndrome of immune deficiency and autoimmunity.
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Biallelic loss of LRBA in humans disrupts B-cell development, activation, plasmablast formation, immunoglobulin secretion, and proliferative responses.
"Individuals with
homozygous LRBA mutations had no LRBA, had disturbed B cell development,
defective in vitro B cell activation, plasmablast formation, and immunoglobulin
secretion, and had low proliferative responses."
Dissecting the localization of lipopolysaccharide-responsive and beige-like anchor protein (LRBA) in the endomembrane system.
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In mononuclear phagocytes, ARF activity controls LRBA trafficking; LRBA is enriched on early and late endosomes and is recruited during early autophagy flux.
"LRBA intracellular trafficking depends on the activity of the GTPase
ADP ribosylation factor-1 (ARF) in MP. LRBA was identified in early, late
endosomes but did not colocalize strongly with lysosomal markers."
Lipopolysaccharide-responsive beige-like anchor acts as a cAMP-dependent protein kinase anchoring protein in B cells.
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LRBA binds PKA RIIbeta in Ramos cells and activation-dependent RIIalpha/RIIbeta in primary human B cells, supporting an AKAP/scaffold role.
"interacting protein. Furthermore, in primary human B cells, LRBA was induced
after CD40L and IL-4 stimulation, and under such activation, we found that LRBA
interacts with RIIα and RIIβ, suggesting that LRBA acts as an AKAP and binds RII
subunits."
Regulation of CTLA-4 recycling by LRBA and Rab11.
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LRBA is required upstream of Rab11 to route CTLA4 into recycling compartments; LRBA loss reduces recycling and shifts CTLA4 toward degradation.
"These results show that LRBA is
required for effective CTLA-4 recycling by delivering CTLA-4 to Rab11 recycling
compartments, and in its absence, CTLA-4 fails to recycle and undergoes
degradation."
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The requirement for LRBA is context dependent: loss produced a stronger CTLA4 phenotype in Jurkat T cells than in HeLa cells, and mouse knockout pathology is limited.
"Interestingly, the importance of LRBA in regulating CTLA‐4 appears to vary in different species and cell types as LRBA KO mice showed limited pathology ... Accordingly, we found that loss of LRBA in Jurkat cells had a much greater effect on CTLA‐4 than in HeLa cells."
Arf1-dependent LRBA recruitment to Rab4 endosomes is required for endolysosome homeostasis.
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ARF-family GTPases recruit LRBA to the trans-Golgi network and Rab4-positive endosomes, where LRBA supports endosomal flow and endolysosome homeostasis.
"We show that LRBA, however, only slightly colocalizes with Rab11. Instead, LRBA
is recruited by members of the small GTPase Arf protein family to the TGN and to
Rab4+ endosomes, where it controls intracellular traffic."
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LRBA-deficient patient fibroblasts accumulate enlarged endolysosomes and show increased lysosome secretion.
"In patient-derived
fibroblasts, loss of LRBA led to defects in the endosomal pathway promoting the
accumulation of enlarged endolysosomes and lysosome secretion."