LRBA is a large BEACH-domain membrane-trafficking scaffold that cycles among cytosolic, trans-Golgi, endosomal, and other endomembrane pools. ARF-family GTPases recruit LRBA to the trans-Golgi network and Rab4-positive endosomes, where it supports endosomal traffic and endolysosome homeostasis. In activated and regulatory human T cells, LRBA routes the inhibitory receptor CTLA4 toward Rab11 recycling compartments and away from lysosomal degradation, thereby maintaining CTLA4 abundance and immune homeostasis. LRBA also participates in ATG9A-vesicle delivery to damaged mitochondria during phagophore growth and PINK1/Parkin mitophagy. In activated human B cells, LRBA binds the regulatory RIIalpha and RIIbeta subunits of protein kinase A and can act as an activation-dependent A-kinase anchoring protein. Biallelic LRBA loss causes an immunodeficiency and autoimmunity syndrome with impaired B-cell activation, plasmablast formation, immunoglobulin secretion, and CTLA4-dependent immune regulation. The LRBA PH-BEACH tandem forms an integrated structural unit, but its PH domain did not bind phospholipids in direct assays. Two reviewed protein isoforms exist, without evidence that the established trafficking or anchoring functions are isoform-specific.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0016020 membrane | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: LRBA has broad membrane association across multiple trafficking compartments. Reason: The phylogenetic membrane assignment is consistent with conserved LRBA-family localization, but GO:0016020 is too broad to define LRBA's core sites of action. Compartment-specific Golgi and endosomal evidence is more informative. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: FB:FBgn0266098 SUPPORTS TRANSFER The Drosophila family source supports conserved membrane-associated trafficking biology. MGI:MGI:1347075 SUPPORTS TRANSFER The mouse family source supports conserved membrane association. MGI:MGI:1933162 SUPPORTS TRANSFER The mouse family source supports conserved membrane association. PANTHER:PTN000348743 SUPPORTS TRANSFER The PANTHER node supports the conserved membrane-associated family assignment. RGD:1562629 SUPPORTS TRANSFER The rat family source supports conserved membrane association. |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: LRBA has a cytosolic pool from which it can be recruited to trafficking membranes. Reason: Cytosolic localization is compatible with LRBA-family biology and with its regulated distribution among cytosol and intracellular membrane compartments. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:1347075 SUPPORTS TRANSFER Mouse LRBA-family localization supports transfer to human LRBA. PANTHER:PTN000348743 SUPPORTS TRANSFER The family node supports conserved cytosolic localization. dictyBase:DDB_G0271502 SUPPORTS TRANSFER The distant family source is consistent with the conservative cytosol term. |
| GO:0000423 mitophagy | IBA GO_REF:0000033 | ACCEPT | Summary: LRBA participates in PINK1/Parkin mitophagy through ATG9A-vesicle trafficking to mitochondria. Reason: The IBA is independently supported by the direct human perturbation study PMID:33773106, which places LRBA among ATG4 proximity partners required for ATG9A trafficking during mitophagy. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN008551111 SUPPORTS TRANSFER The phylogenetic node agrees with direct human LRBA mitophagy evidence. UniProtKB:P50851 SUPPORTS TRANSFER Self-reference: the target is its own IBD seed, which is expected rather than circular -- its own IMP annotation to this term is one of the descendant evidences behind the IBD. The IBA then asserts the additional claim that the function is inherited rather than lineage-specific. |
| GO:0019901 protein kinase binding | IBA GO_REF:0000033 | MODIFY | Summary: GO:0019901 implies binding to a catalytic protein kinase enzyme, whereas direct human B-cell evidence demonstrates binding to the regulatory RIIalpha and RIIbeta subunits of protein kinase A. Reason: PMID:32592188 does not establish LRBA binding to the catalytic protein kinase enzyme required by GO:0019901. It directly shows activation-dependent binding of human LRBA to PKA RIIalpha and RIIbeta; GO:0034237 exactly captures binding to protein kinase A regulatory subunits without conflating them with the catalytic kinase. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:1347075 SUPPORTS SOURCE BUT NOT TARGET The mouse family source supports broad kinase binding but does not establish human LRBA specificity for PKA regulatory subunits. PANTHER:PTN000348581 SOURCE WEAK OR INFERRED The phylogenetic node supports only the broad ancestral binding term; direct human evidence is required for the more informative PKA RII specificity. Proposed replacements: protein kinase A regulatory subunit binding Supporting Evidence: PMID:32592188 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 RIIΞ± and RIIΞ², suggesting that LRBA acts as an AKAP and binds RII subunits. |
| GO:0034497 protein localization to phagophore assembly site | IBA GO_REF:0000033 | ACCEPT | Summary: LRBA promotes ATG9A localization to the phagophore assembly site during mitophagy. Reason: The phylogenetic assignment is independently supported by human LRBA perturbation in PMID:33773106 and captures a proximal trafficking step rather than a broad downstream autophagy phenotype. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN008551111 SUPPORTS TRANSFER The phylogenetic node agrees with direct human LRBA evidence for this step. UniProtKB:P50851 SUPPORTS TRANSFER Self-reference: the target is its own IBD seed, which is expected rather than circular -- its own IMP annotation to this term is one of the descendant evidences behind the IBD. The IBA then asserts the additional claim that the function is inherited rather than lineage-specific. |
| GO:0005765 lysosomal membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Inferred evidence supports a lysosomal-membrane pool, but direct human LRBA localization there is weak. Reason: The UniProt subcellular-location mapping is retained, but CTLA4 lysosomal degradation describes cargo fate rather than LRBA residence. Direct human imaging found only weak colocalization with lysosomal markers, so this inferred compartment is non-core. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB-SubCell:SL-0157 SUPPORTS TRANSFER Exact UniProt vocabulary mapping for lysosomal membrane. |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Inferred evidence supports an ER-membrane pool of LRBA outside its best-resolved core compartments. Reason: The conservative UniProt mapping agrees with ortholog-based localization, but the human ATG9A study does not directly establish LRBA residence at the ER membrane. The inferred location is therefore retained as non-core. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB-SubCell:SL-0097 SUPPORTS TRANSFER Exact UniProt vocabulary mapping for endoplasmic reticulum membrane. |
| GO:0005794 Golgi apparatus | IEA GO_REF:0000120 | ACCEPT | Summary: LRBA localizes to the Golgi apparatus, a central compartment in its Golgi-endosomal trafficking role. Reason: The combined electronic annotation agrees with direct HPA Golgi localization and with PMID:31263572, which places LRBA mainly in a Golgi/trans-Golgi transport context. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00028708 SUPPORTS TRANSFER The ARBA source supports the conservative Golgi localization. UniProtKB-SubCell:SL-0132 SUPPORTS TRANSFER Exact UniProt vocabulary source for Golgi localization. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: A plasma-membrane pool of LRBA is conserved but is secondary to its intracellular trafficking locations. Reason: The UniProt mapping is biologically defensible and agrees with ortholog transfer, but current human mechanistic evidence centers intracellular CTLA4 recycling and mitophagy rather than a constitutive plasma-membrane activity. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB-SubCell:SL-0039 SUPPORTS TRANSFER Exact UniProt vocabulary mapping for plasma membrane. |
| GO:0005515 protein binding | IPI PMID:26206937 AUTOIMMUNE DISEASE. Patients with LRBA deficiency show CTLA4... | KEEP AS NON CORE | Summary: Focused disease-mechanism work identified a physical LRBA-CTLA4 interaction in endosomal vesicles. Reason: PMID:26206937 directly supports the interaction and its importance for CTLA4 turnover, but GO:0005515 is too generic to represent LRBA's trafficking mechanism. The valid interaction is retained as non-core rather than promoted as a defining molecular activity. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: A proteome-scale interaction map recovered CTLA4 as an LRBA partner. Reason: The screen is compatible with focused LRBA-CTLA4 evidence, but generic protein binding adds no informative molecular-function description and the large-scale assay alone does not define the trafficking mechanism. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | MARK AS OVER ANNOTATED | Summary: A multimodal cell-map screen recovered CTLA4 as an LRBA interaction partner. Reason: The screen corroborates a known LRBA-CTLA4 relationship but does not improve on the focused trafficking evidence, and generic protein binding is not an informative activity term. |
| GO:0005794 Golgi apparatus | IDA GO_REF:0000052 | ACCEPT | Summary: Human Protein Atlas immunofluorescence directly localizes LRBA to the Golgi apparatus. Reason: The experimentally curated human localization agrees with the Golgi/trans-Golgi context reported for LRBA trafficking and is a core intracellular location. |
| GO:0005765 lysosomal membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Ortholog evidence supports a possible lysosomal-membrane pool of human LRBA. Reason: Transfer from mouse Lrba is defensible, but direct human LRBA shows weak lysosomal-marker colocalization, and CTLA4 delivery to degradation does not establish LRBA residence at the lysosomal membrane. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q9ESE1 SUPPORTS TRANSFER Mouse Lrba supports conserved lysosomal-membrane localization. |
| GO:0005789 endoplasmic reticulum membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Ortholog evidence supports a possible ER-membrane pool of human LRBA. Reason: Mouse Lrba is an appropriate ortholog source, but current human ATG9A trafficking evidence does not directly localize LRBA to the ER membrane. The transferred compartment is retained as non-core. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q9ESE1 SUPPORTS TRANSFER Mouse Lrba supports conserved ER-membrane localization. |
| GO:0005886 plasma membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Ortholog evidence supports a plasma-membrane pool of LRBA. Reason: The transfer from mouse Lrba is defensible, but plasma-membrane localization is secondary to the intracellular Golgi-endosomal and autophagy compartments where human LRBA mechanisms have been established. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q9ESE1 SUPPORTS TRANSFER Mouse Lrba supports a conserved but non-core plasma-membrane pool. |
| GO:0005515 protein binding | IPI PMID:31263572 Dominant TOM1 mutation associated with combined immunodefici... | KEEP AS NON CORE | Summary: Proximity proteomics placed LRBA with TOM1 in a Golgi-endosomal trafficking context. Reason: PMID:31263572 reports LRBA-TOM1 proximity within a broader trafficking map, but generic protein binding is not a defining LRBA activity and the assay does not establish an obligate stable complex. |
| GO:0000423 mitophagy | IMP PMID:33773106 ATG4 family proteins drive phagophore growth independently o... | ACCEPT | Summary: Human LRBA perturbation supports a role in PINK1/Parkin mitophagy. Reason: PMID:33773106 directly places LRBA among ATG4 proximity partners involved in ATG9A-vesicle trafficking to mitochondria, a proximal requirement for phagophore growth during mitophagy. Supporting Evidence: PMID:33773106 ATG4 proximity networks reveal a role for ATG4s and their proximity partners, including the immune-disease protein LRBA, in ATG9A vesicle trafficking to mitochondria. |
| GO:0034497 protein localization to phagophore assembly site | IMP PMID:33773106 ATG4 family proteins drive phagophore growth independently o... | ACCEPT | Summary: LRBA is required for ATG9A localization to the phagophore assembly site during mitophagy. Reason: The human perturbation evidence in PMID:33773106 supports this specific trafficking step and is more informative than a broad autophagy annotation. Supporting Evidence: PMID:33773106 ATG4 proximity networks reveal a role for ATG4s and their proximity partners, including the immune-disease protein LRBA, in ATG9A vesicle trafficking to mitochondria. |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | KEEP AS NON CORE | Summary: NK-cell membrane proteomics detected LRBA in a broad membrane-enriched fraction. Reason: The high-throughput human immune-cell dataset supports membrane association, but GO:0016020 does not identify the relevant membrane subtype. It is retained as non-core in favor of direct Golgi and endosomal localization evidence. |
| GO:0032456 endocytic recycling | IMP PMID:33960403 Regulation of CTLA-4 recycling by LRBA and Rab11. | NEW | Summary: Human LRBA is required for constitutive endocytic recycling of CTLA4 through Rab11 compartments. Reason: LRBA loss impairs constitutive CTLA4 recycling and redirects the internalized receptor toward degradation in human-cell experiments. GO:0032456 captures the endocytic recycling route without asserting that LRBA is a constitutive Rab11 component. Supporting Evidence: PMID:33960403 Overall, we find that in the absence of ligand, constitutive CTLAβ4 trafficking adopts many of the hallmark pathways seen for other clathrinβmediated endocytic receptors. However, CTLAβ4 is specifically dependent on LRBA to permit effective recycling via a Rab11 compartment. |
| GO:0005768 endosome | IDA PMID:31883622 Dissecting the localization of lipopolysaccharide-responsive... | NEW | Summary: Human LRBA localizes to early and late endosomes in mononuclear phagocytes. Reason: Direct compartment analysis places LRBA in both early and late endosomes. The general endosome term is appropriate because localization spans multiple endosomal stages and is explicitly distinguished from strong lysosome overlap. Supporting Evidence: PMID:31883622 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. |
| GO:0034237 protein kinase A regulatory subunit binding | IPI PMID:32592188 Lipopolysaccharide-responsive beige-like anchor acts as a cA... | NEW | Summary: Activated human B cells show LRBA binding to protein kinase A RII regulatory subunits. Reason: Direct human B-cell interaction evidence supports the precise PKA regulatory subunit binding term. The annotation is activation-contextual and does not imply kinase activity or a constitutive stable LRBA-PKA complex. Supporting Evidence: PMID:32592188 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 RIIΞ± and RIIΞ², suggesting that LRBA acts as an AKAP and binds RII subunits. |
| GO:0016197 endosomal transport | IMP PMID:39325073 Arf1-dependent LRBA recruitment to Rab4 endosomes is require... | NEW | Summary: Human LRBA is required for normal transport flow through the endosomal system. Reason: LRBA loss in patient-derived fibroblasts disrupts the endosomal pathway and causes enlarged endolysosomes and increased lysosome secretion, while ARF1/3- dependent recruitment places LRBA on Rab4-positive endosomes. GO:0016197 captures the directly tested general endosomal transport role without asserting a stable complex or continuity with CTLA4/Rab11 recycling. Supporting Evidence: PMID:39325073 In patient-derived fibroblasts, loss of LRBA led to defects in the endosomal pathway promoting the accumulation of enlarged endolysosomes and lysosome secretion. |
| GO:0005802 trans-Golgi network | IDA PMID:39325073 Arf1-dependent LRBA recruitment to Rab4 endosomes is require... | NEW | Summary: Endogenous human LRBA localizes mainly to the trans-Golgi network in healthy-donor fibroblasts. Reason: Direct immunofluorescence of endogenous LRBA in two healthy human donor fibroblast lines places the protein mainly at the TGN. GO:0005802 is preferred over the membrane-specific child because the experiment establishes compartment localization without resolving bilayer association. Supporting Evidence: PMID:39325073 In cells obtained from two healthy donors, LRBA localized mainly to the trans-Golgi network (TGN), as observed previously (Wang et al., 2001; Lo et al., 2015; Kurtenbach et al., 2017) (Fig. 1 D). |
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Download this section (compressed HTML)Q: Does LRBA bind CTLA4 or a CTLA4-selective sorting adaptor directly to enable constitutive entry into Rab11 recycling compartments?
Q: Which endogenous cargoes besides CTLA4 require LRBA for endosomal recycling and endolysosome homeostasis in immune and nonimmune human cells?
Q: Does LRBA use the same domains and partners for ATG9A trafficking during mitophagy as for CTLA4/endosomal traffic?
Q: Which PKA substrates and B-cell responses depend specifically on LRBA-RII anchoring?
Q: Are either of the two reviewed LRBA protein isoforms specialized for trafficking, autophagy, or PKA anchoring?
Experiment: Endogenously tag LRBA and CTLA4 in primary human T cells, combine pulse-chase surface labeling with live Rab11 imaging, and rescue acute LRBA loss with candidate cargo-binding mutants.
Hypothesis: LRBA selects CTLA4 through a cargo-specific contact required for entry into the Rab11 recycling route.
Type: Endogenous live-cell trafficking and separation-of-function rescue
Experiment: Apply quantitative surface proteomics and recycling assays after acute LRBA degradation in primary T cells, B cells, and patient-corrected fibroblasts, with CTLA4 as a positive control.
Hypothesis: LRBA controls a broader, cell-type-dependent endosomal recycling cargo set.
Type: Comparative trafficking proteomics
Experiment: Synchronize PINK1/Parkin mitophagy in endogenously tagged human cells and combine single-particle ATG9A tracking, LRBA acute depletion, proximity labeling, and domain-specific rescue.
Hypothesis: LRBA directly scaffolds an ATG9A capture or transfer step during mitophagy.
Type: Mitophagy trafficking kinetics and interactomics
Experiment: Use compartment-targeted PKA biosensors and phosphoproteomics in CD40L/IL-4- activated primary B cells after LRBA depletion and rescue with RII-binding-deficient mutants.
Hypothesis: Activation-dependent LRBA-RII binding creates a spatially restricted PKA signaling domain required for human B-cell responses.
Type: Spatial signaling and phosphoproteomics
Experiment: Develop isoform-specific proteomic reagents and perform expression-matched isoform rescue for CTLA4 recycling, ATG9A trafficking, and PKA anchoring.
Hypothesis: LRBA isoforms differ in abundance or function across immune-cell states.
Type: Isoform-resolved proteomics and functional rescue
What is not known β curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The direct molecular contacts by which LRBA selects CTLA4 and enables its entry into Rab11-dependent recycling are unknown.
OPEN BIOLOGY MF_DARK
What is known: Human loss-of-function experiments establish constitutive CTLA4 recycling failure and reduced entry into Rab11 compartments, but do not identify a direct LRBA cargo contact or sorting partner.
Significance: Resolving these contacts would distinguish cargo recognition from coat recruitment, membrane remodeling, or another scaffold mechanism.
What would resolve it: Map endogenous LRBA contacts with CTLA4, Rab11 machinery, and sorting adaptors using separation-of-function mutants and purified-component assays.
Provenance (the field's own admissions):
Gap: The molecular basis for LRBA-mediated endolysosome homeostasis beyond CTLA4 cargo is unresolved, including the relevant cargo spectrum and membrane-remodeling step.
OPEN BIOLOGY MF_DARK
What is known: LRBA-deficient human fibroblasts accumulate enlarged endolysosomes and increase lysosome secretion, but these phenotypes do not identify a direct LRBA activity.
Significance: This would establish whether CTLA4 is one client of a general LRBA sorting system or uses an immune-cell-specialized pathway.
What would resolve it: Perform quantitative surface/recycling proteomics and organelle-resolved lipid and cargo flux analyses after acute endogenous LRBA depletion and rescue.
Provenance (the field's own admissions):
Gap: LRBA's direct role in ATG9A-vesicle capture, movement, or fusion at damaged mitochondria and the phagophore assembly site is unknown.
OPEN BIOLOGY MF_DARK
What is known: Functional proximity experiments establish an LRBA requirement in ATG9A-vesicle trafficking during mitophagy but do not reveal its direct molecular activity.
Significance: Defining the step would connect LRBA's autophagy role to, or separate it from, its endosomal sorting mechanism.
What would resolve it: Use synchronized mitophagy, endogenous live-cell LRBA/ATG9A imaging, acute depletion, and domain-rescue analysis to resolve recruitment and fusion kinetics.
Provenance (the field's own admissions):
Gap: The physiological outputs and spatial organization of LRBA-dependent PKA RII anchoring in primary B cells are unknown.
OPEN BIOLOGY BP_DARK
What is known: Activation-dependent binding to RIIalpha and RIIbeta is demonstrated in human B cells, but no LRBA-organized PKA substrate or signaling microdomain is established.
Significance: This is necessary to connect the anchoring interaction to B-cell activation and to distinguish it from incidental coimmunoprecipitation.
What would resolve it: Compare local PKA activity and phosphoproteomes in activated primary B cells after LRBA depletion and rescue with RII-binding-deficient LRBA mutants.
Provenance (the field's own admissions):
Gap: Functional differences between the two reviewed LRBA protein isoforms have not been established.
OPEN BIOLOGY BP_DARK
What is known: UniProt records two protein isoforms, whereas available trafficking, mitophagy, and PKA-anchoring studies do not assign these functions to a particular isoform.
Significance: Isoform-resolved evidence is needed before any function or disease mechanism is attributed selectively to one product.
What would resolve it: Quantify endogenous isoform expression across immune lineages and perform isoform-specific rescue of CTLA4 recycling, ATG9A trafficking, and PKA anchoring.
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