LRRC8A (SWELL1) is the obligatory, pore-forming subunit of the volume-regulated anion channel (VRAC, also called VSOAC or I(Cl,swell)), the channel that lets vertebrate cells shed chloride and organic osmolytes and so recover their volume after swelling. It is a four-pass membrane protein with a large cytosolic leucine-rich-repeat domain and assembles into hexamers built as a trimer of dimers, with a symmetry mismatch between the transmembrane pore domain and the LRR domains. LRRC8A cannot support channel activity by itself in cells: it must heteromerise with one or more of LRRC8B-E, and the subunit combination determines inactivation kinetics, single-channel conductance and substrate preference, although purified homohexameric LRRC8A does conduct anions in reconstituted membranes. The channel opens on hypotonic swelling and on a fall in cytoplasmic ionic strength. Its pore is wide and poorly selective, so beyond chloride and iodide it passes taurine, myo-inositol, glutamate, aspartate, GABA and D-serine, the drug cisplatin, and the innate immune second messenger 2'3'-cGAMP. cGAMP permeation is promoted by LRRC8C and LRRC8E subunits and suppressed by LRRC8D; how much of cGAMP traffic in vivo runs through VRAC is disputed, being dominant in some tumour cell lines and negligible in others, and dispensable for antitumour immunity in at least one mouse model. Besides the plasma membrane, a subset of LRRC8 channels resides on lysosomal membranes, where they generate lysosomal VRAC currents and support formation of the large vacuoles that buffer cytosolic water. Loss of LRRC8A has broad physiological consequences: a truncating human allele causes congenital agammaglobulinemia by blocking the pro-B to pre-B cell transition, and rodent models implicate it in glucose-stimulated insulin secretion, adipocyte and myoblast differentiation and spermatogenesis.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic assertion that the protein is active in the cytoplasm. Reason: Defensible but uninformative. LRRC8A is an integral membrane protein whose large leucine-rich-repeat domains face the cytosol, and the Lyso-VRAC pool lies on an organelle within the cytoplasm, so the assertion is not false; it is simply far less useful than the plasma-membrane and lysosomal-membrane annotations this gene already carries. Retained without a corrective action because the PAINT tree behind this IBA was not inspected and no propagation-level defect can honestly be asserted. Supporting Evidence: PMID:30095067 The structure reveals a trimer of dimers assembly with symmetry mismatch between the pore-forming domain and the cytosolic leucine-rich repeat (LRR) domains. |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: LRRC8A is a polytopic plasma-membrane protein; this is where the swelling-activated channel operates. Reason: Core location, supported by imaging, surface labelling and electrophysiology in multiple independent studies. Supporting Evidence: PMID:24725410 SWELL1 is localized to the plasma membrane, and its knockdown dramatically reduces endogenous VRAC currents and regulatory cell volume decrease in various cell types. |
| GO:0005225 volume-sensitive anion channel activity | IBA GO_REF:0000033 | ACCEPT | Summary: LRRC8A is the obligatory subunit of the volume-regulated anion channel; loss of LRRC8A ablates swelling-activated anion current in every cell type tested, and LRRC8A-containing hexamers reconstitute it. Reason: Core molecular function, established independently by two 2014 screens and confirmed by reconstitution, cryo-EM and structure-function analysis. Note that LRRC8A does not act alone in cells: VRAC currents are only restored when LRRC8A is co-expressed with LRRC8B-E, and subunit composition sets kinetics and substrate preference. Purified homohexameric LRRC8A nevertheless conducts anions in reconstituted systems, so the enables qualifier is defensible, but the physiological channel is a heteromer and this is recorded in core_functions with contributes_to plus in_complex. Supporting Evidence: PMID:24725410 We identified SWELL1 (LRRC8A), a member of a four-transmembrane protein family with unknown function, as essential for hypotonicity-induced iodide influx. PMID:24790029 Genomic disruption of LRRC8A ablated VRAC currents. |
| GO:0034702 monoatomic ion channel complex | IBA GO_REF:0000033 | ACCEPT | Summary: LRRC8A assembles into a hexameric ion channel complex with LRRC8B-E. Reason: Correct and central: the functional unit is the LRRC8 hexamer, confirmed biochemically and by cryo-EM. Supporting Evidence: PMID:30095067 Here, we report a high-resolution cryo-electron microscopy structure of full-length human homo-hexameric SWELL1. PMID:26824658 we show that SWELL1 and up to four other LRRC8 subunits assemble into heterogeneous complexes of |
| GO:0098656 monoatomic anion transmembrane transport | IBA GO_REF:0000033 | ACCEPT | Summary: Anion movement across the membrane is the direct consequence of VRAC opening. Reason: Core biological process, matching the molecular function. Supporting Evidence: PMID:24725410 We identified SWELL1 (LRRC8A), a member of a four-transmembrane protein family with unknown function, as essential for hypotonicity-induced iodide influx. |
| GO:0140361 cyclic-GMP-AMP transmembrane import across plasma membrane | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Import of extracellular cGAMP across the plasma membrane through LRRC8A-containing VRACs, feeding STING activation; real, but not required for every cGAMP-dependent process in vivo. Reason: Contested, and the dispute is about physiological requirement, not about the transport itself. Lahey et al. 2020 established VRAC as a widely expressed cGAMP transporter whose activity depends on subunit composition - promoted by LRRC8C/LRRC8E and suppressed by LRRC8D (PMID:33171122) - and two independent groups reported in vivo loss-of-function phenotypes consistent with it (Lrrc8e-deficient mice with impaired interferon responses to HSV-1, PMID:32277911; LRRC8C-dependent cGAMP uptake shaping T cell function, PMID:35105987). Thöne et al. 2026 is frequently read as refuting this, but it does not: in the same study, Lrrc8a disruption at endogenous expression showed that VRAC is the dominant plasma-membrane cGAMP transporter of MC38 cells, while tumour growth and the cGAMP-dependent antitumour response were nonetheless unaffected by loss of tumour- or host-expressed VRAC (PMID:41419196). A knockout showing that a physiological outcome proceeds without a protein does not show the protein cannot transport the substrate; it bounds the in vivo requirement. Consistent with that, the same authors accept a pivotal VRAC-dependent role after irradiation, and find B16-F10 cells barely use VRAC for cGAMP, i.e. the contribution is cell-type and context dependent. A 2025 study independently treats VRAC-mediated cGAMP transport as real and tunable, identifying PSA/NPEPPS as an inhibitory auxiliary subunit (PMID:41371222). Retained as a genuine molecular capability, but demoted from core: it is one permeant among many for a large-pore, broadly selective channel, it is a property of particular LRRC8A-containing heteromers rather than of LRRC8A as such, and its in vivo weight varies by cell type and stimulus. Supporting Evidence: PMID:41419196 We conclude that VRAC is the dominant PM cGAMP transporter of MC38 cells. PMID:41419196 However, tumor growth and the cGAMP-mediated antitumor immune response were independent of both tumor- and host-expressed VRAC. |
| GO:0015810 aspartate transmembrane transport | IBA GO_REF:0000033 | ACCEPT | Summary: Aspartate (and glutamate) efflux through LRRC8 channels under osmotic stress. Reason: Supported by subunit-resolved substrate profiling of LRRC8 heteromers; part of the same organic-osmolyte and amino-acid release function as taurine, and recorded by UniProt as an L-aspartate transport reaction. Supporting Evidence: PMID:28193731 We show that, besides the osmolytes taurine and myo-inositol, LRRC8 channels transport the neurotransmitters glutamate, aspartate and PMID:28193731 flux of negatively charged aspartate was equally well supported by LRRC8E |
| GO:0005765 lysosomal membrane | IEA GO_REF:0000044 | ACCEPT | Summary: A distinct intracellular pool of LRRC8 proteins on lysosomal membranes carries Lyso-VRAC currents. Reason: Genuine second site of action, demonstrated with a C-terminal di-leucine targeting mutant that removes Lyso-VRAC currents while leaving plasma-membrane VRAC intact. Supporting Evidence: PMID:33139539 LRRC8 proteins on lysosome membranes generate large lysosomal volume-regulated anion channel (Lyso-VRAC) currents in response to low cytoplasmic ionic strength conditions. PMID:33139539 We demonstrate that intracellular LRRC8 proteins acting within lysosomes also play an essential role in cellular osmoregulation. |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: LRRC8A is a polytopic plasma-membrane protein; this is where the swelling-activated channel operates. Reason: Core location, supported by imaging, surface labelling and electrophysiology in multiple independent studies. Supporting Evidence: PMID:24725410 SWELL1 is localized to the plasma membrane, and its knockdown dramatically reduces endogenous VRAC currents and regulatory cell volume decrease in various cell types. |
| GO:0005515 protein binding | IPI PMID:24790029 Identification of LRRC8 heteromers as an essential component... | REMOVE | Summary: Bare protein binding from interaction screens and from the LRRC8 heteromerisation work. Reason: Per project curation guidance, protein binding carries no functional information. The biology behind these rows - LRRC8A heteromerising with LRRC8B/C/D/E - is already represented by GO:0034702 monoatomic ion channel complex and GO:0034214 protein hexamerization. No more informative molecular function is supportable from this evidence, so the row is removed rather than rewritten. Removal does not imply the reported interaction is false. Supporting Evidence: PMID:24790029 LRRC8A formed heteromers with other LRRC8 multispan membrane proteins. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: Bare protein binding from interaction screens and from the LRRC8 heteromerisation work. Reason: Per project curation guidance, protein binding carries no functional information. The biology behind these rows - LRRC8A heteromerising with LRRC8B/C/D/E - is already represented by GO:0034702 monoatomic ion channel complex and GO:0034214 protein hexamerization. No more informative molecular function is supportable from this evidence, so the row is removed rather than rewritten. Removal does not imply the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: Bare protein binding from interaction screens and from the LRRC8 heteromerisation work. Reason: Per project curation guidance, protein binding carries no functional information. The biology behind these rows - LRRC8A heteromerising with LRRC8B/C/D/E - is already represented by GO:0034702 monoatomic ion channel complex and GO:0034214 protein hexamerization. No more informative molecular function is supportable from this evidence, so the row is removed rather than rewritten. Removal does not imply the reported interaction is false. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | REMOVE | Summary: Bare protein binding from interaction screens and from the LRRC8 heteromerisation work. Reason: Per project curation guidance, protein binding carries no functional information. The biology behind these rows - LRRC8A heteromerising with LRRC8B/C/D/E - is already represented by GO:0034702 monoatomic ion channel complex and GO:0034214 protein hexamerization. No more informative molecular function is supportable from this evidence, so the row is removed rather than rewritten. Removal does not imply the reported interaction is false. |
| GO:0042802 identical protein binding | IPI PMID:24790029 Identification of LRRC8 heteromers as an essential component... | KEEP AS NON CORE | Summary: LRRC8A self-associates; homo-hexamers are the form solved by cryo-EM. Reason: Unlike bare protein binding this is informative, since LRRC8A homo-oligomerisation is a real and structurally characterised property. It is nevertheless an assembly property already captured more precisely by GO:0034214 and GO:0034702, so it is not itself a core function. Supporting Evidence: PMID:26824658 we show that SWELL1 and up to four other LRRC8 subunits assemble into heterogeneous complexes of |
| GO:0042802 identical protein binding | IPI PMID:30095067 Structure of the human volume regulated anion channel. | KEEP AS NON CORE | Summary: LRRC8A self-associates; homo-hexamers are the form solved by cryo-EM. Reason: Unlike bare protein binding this is informative, since LRRC8A homo-oligomerisation is a real and structurally characterised property. It is nevertheless an assembly property already captured more precisely by GO:0034214 and GO:0034702, so it is not itself a core function. Supporting Evidence: PMID:30095067 Here, we report a high-resolution cryo-electron microscopy structure of full-length human homo-hexameric SWELL1. |
| GO:0042802 identical protein binding | IPI PMID:30127360 Cryo-EM structures of the human volume-regulated anion chann... | KEEP AS NON CORE | Summary: LRRC8A self-associates; homo-hexamers are the form solved by cryo-EM. Reason: Unlike bare protein binding this is informative, since LRRC8A homo-oligomerisation is a real and structurally characterised property. It is nevertheless an assembly property already captured more precisely by GO:0034214 and GO:0034702, so it is not itself a core function. Supporting Evidence: PMID:26824658 we show that SWELL1 and up to four other LRRC8 subunits assemble into heterogeneous complexes of |
| GO:0001678 intracellular glucose homeostasis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: VRAC activity in insulin-target and beta cells influences glucose handling; transferred from mouse. Reason: Real but distal to the molecular function: a downstream organismal or tissue-level consequence of VRAC-mediated anion and osmolyte flux, transferred from the mouse or rat ortholog. Supporting Evidence: PMID:29371604 SWELL1 depletion in MIN6 cells and islets significantly impairs glucose-stimulated insulin secretion. |
| GO:0002329 pre-B cell differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: LRRC8A is required for the pro-B to pre-B cell transition; a truncating human allele causes agammaglobulinemia. Reason: Real but distal to the molecular function: a downstream organismal or tissue-level consequence of VRAC-mediated anion and osmolyte flux, transferred from the mouse or rat ortholog. Well documented for this gene in human and mouse, but it is a developmental requirement downstream of channel activity rather than the activity itself. Note that disrupting the non-obligatory LRRC8B-E subunits has no detectable effect on T or B cell development, which argues the phenotype tracks LRRC8A specifically. Supporting Evidence: PMID:14660746 These results indicate that LRRC8 is responsible for the B cell deficiency in this patient and is required for B cell development. PMID:41419196 Disruption of any of the non-essential subunits, LRRC8B-LRRC8E, had no discernible effect on T or B cell development in mice. |
| GO:0005225 volume-sensitive anion channel activity | IEA GO_REF:0000120 | ACCEPT | Summary: LRRC8A is the obligatory subunit of the volume-regulated anion channel; loss of LRRC8A ablates swelling-activated anion current in every cell type tested, and LRRC8A-containing hexamers reconstitute it. Reason: Core molecular function, established independently by two 2014 screens and confirmed by reconstitution, cryo-EM and structure-function analysis. Note that LRRC8A does not act alone in cells: VRAC currents are only restored when LRRC8A is co-expressed with LRRC8B-E, and subunit composition sets kinetics and substrate preference. Purified homohexameric LRRC8A nevertheless conducts anions in reconstituted systems, so the enables qualifier is defensible, but the physiological channel is a heteromer and this is recorded in core_functions with contributes_to plus in_complex. Supporting Evidence: PMID:24725410 We identified SWELL1 (LRRC8A), a member of a four-transmembrane protein family with unknown function, as essential for hypotonicity-induced iodide influx. PMID:24790029 Genomic disruption of LRRC8A ablated VRAC currents. |
| GO:0006970 response to osmotic stress | IEA GO_REF:0000107 | ACCEPT | Summary: VRAC is activated by osmotic swelling and by reduced cytoplasmic ionic strength. Reason: Core biological process; the stimulus that gates the channel. |
| GO:0007283 spermatogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Spermatogenesis defect in the mouse ortholog, transferred by similarity. Reason: Real but distal to the molecular function: a downstream organismal or tissue-level consequence of VRAC-mediated anion and osmolyte flux, transferred from the mouse or rat ortholog. No human-specific evidence; kept because loss of an obligatory osmoregulatory channel plausibly impairs germ-cell development, but it is a tissue-level phenotype. |
| GO:0015734 taurine transmembrane transport | IEA GO_REF:0000107 | ACCEPT | Summary: Taurine efflux through LRRC8 channels, one of the defining VSOAC organic-osmolyte fluxes. Reason: Well supported: taurine flux depends on LRRC8 proteins in human cells, and subunit-resolved work confirms taurine as an LRRC8 substrate. This is part of the core osmolyte-release function, not a peripheral claim. Supporting Evidence: PMID:24790029 Taurine flux and regulatory volume decrease also depended on LRRC8 proteins. PMID:28193731 We show that, besides the osmolytes taurine and myo-inositol, LRRC8 channels transport the neurotransmitters glutamate, aspartate and |
| GO:0015810 aspartate transmembrane transport | IEA GO_REF:0000107 | ACCEPT | Summary: Aspartate (and glutamate) efflux through LRRC8 channels under osmotic stress. Reason: Supported by subunit-resolved substrate profiling of LRRC8 heteromers; part of the same organic-osmolyte and amino-acid release function as taurine, and recorded by UniProt as an L-aspartate transport reaction. Supporting Evidence: PMID:28193731 We show that, besides the osmolytes taurine and myo-inositol, LRRC8 channels transport the neurotransmitters glutamate, aspartate and PMID:28193731 flux of negatively charged aspartate was equally well supported by LRRC8E |
| GO:0032024 positive regulation of insulin secretion | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: SWELL1-mediated swell-activated chloride current depolarises beta cells and supports glucose-stimulated insulin secretion. Reason: Real but distal to the molecular function: a downstream organismal or tissue-level consequence of VRAC-mediated anion and osmolyte flux, transferred from the mouse or rat ortholog. Supporting Evidence: PMID:29371604 we show that SWELL1 mediates a swell-activated, depolarizing chloride current PMID:29371604 SWELL1 depletion in MIN6 cells and islets significantly impairs glucose-stimulated insulin secretion. |
| GO:0034214 protein hexamerization | IEA GO_REF:0000107 | ACCEPT | Summary: LRRC8A forms a hexamer (homo-hexameric in the reported structures, hetero-hexameric in cells). Reason: Directly demonstrated by cryo-EM of full-length human LRRC8A and by size determination of native complexes; the hexameric assembly is what creates the conduction pathway. Supporting Evidence: PMID:26824658 we show that SWELL1 and up to four other LRRC8 subunits assemble into heterogeneous complexes of |
| GO:0034702 monoatomic ion channel complex | IEA GO_REF:0000107 | ACCEPT | Summary: LRRC8A assembles into a hexameric ion channel complex with LRRC8B-E. Reason: Correct and central: the functional unit is the LRRC8 hexamer, confirmed biochemically and by cryo-EM. Supporting Evidence: PMID:30095067 Here, we report a high-resolution cryo-electron microscopy structure of full-length human homo-hexameric SWELL1. PMID:26824658 we show that SWELL1 and up to four other LRRC8 subunits assemble into heterogeneous complexes of |
| GO:0042802 identical protein binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: LRRC8A self-associates; homo-hexamers are the form solved by cryo-EM. Reason: Unlike bare protein binding this is informative, since LRRC8A homo-oligomerisation is a real and structurally characterised property. It is nevertheless an assembly property already captured more precisely by GO:0034214 and GO:0034702, so it is not itself a core function. Supporting Evidence: PMID:26824658 we show that SWELL1 and up to four other LRRC8 subunits assemble into heterogeneous complexes of |
| GO:0045663 positive regulation of myoblast differentiation | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Myoblast differentiation phenotype transferred from the mouse ortholog. Reason: Real but distal to the molecular function: a downstream organismal or tissue-level consequence of VRAC-mediated anion and osmolyte flux, transferred from the mouse or rat ortholog. |
| GO:0098656 monoatomic anion transmembrane transport | IEA GO_REF:0000107 | ACCEPT | Summary: Anion movement across the membrane is the direct consequence of VRAC opening. Reason: Core biological process, matching the molecular function. Supporting Evidence: PMID:24725410 We identified SWELL1 (LRRC8A), a member of a four-transmembrane protein family with unknown function, as essential for hypotonicity-induced iodide influx. |
| GO:0140360 cyclic-GMP-AMP transmembrane transporter activity | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: VRAC channels containing LRRC8A together with LRRC8C or LRRC8E transport 2'3'-cGAMP; the activity is real but its physiological weight is disputed. Reason: Contested, and the dispute is about physiological requirement, not about the transport itself. Lahey et al. 2020 established VRAC as a widely expressed cGAMP transporter whose activity depends on subunit composition - promoted by LRRC8C/LRRC8E and suppressed by LRRC8D (PMID:33171122) - and two independent groups reported in vivo loss-of-function phenotypes consistent with it (Lrrc8e-deficient mice with impaired interferon responses to HSV-1, PMID:32277911; LRRC8C-dependent cGAMP uptake shaping T cell function, PMID:35105987). Thöne et al. 2026 is frequently read as refuting this, but it does not: in the same study, Lrrc8a disruption at endogenous expression showed that VRAC is the dominant plasma-membrane cGAMP transporter of MC38 cells, while tumour growth and the cGAMP-dependent antitumour response were nonetheless unaffected by loss of tumour- or host-expressed VRAC (PMID:41419196). A knockout showing that a physiological outcome proceeds without a protein does not show the protein cannot transport the substrate; it bounds the in vivo requirement. Consistent with that, the same authors accept a pivotal VRAC-dependent role after irradiation, and find B16-F10 cells barely use VRAC for cGAMP, i.e. the contribution is cell-type and context dependent. A 2025 study independently treats VRAC-mediated cGAMP transport as real and tunable, identifying PSA/NPEPPS as an inhibitory auxiliary subunit (PMID:41371222). Retained as a genuine molecular capability, but demoted from core: it is one permeant among many for a large-pore, broadly selective channel, it is a property of particular LRRC8A-containing heteromers rather than of LRRC8A as such, and its in vivo weight varies by cell type and stimulus. Supporting Evidence: PMID:33171122 Here, we identify LRRC8A heteromeric channels, better known as volume-regulated anion channels (VRAC), as widely expressed cGAMP transporters. PMID:41419196 We conclude that VRAC is the dominant PM cGAMP transporter of MC38 cells. |
| GO:0140361 cyclic-GMP-AMP transmembrane import across plasma membrane | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Import of extracellular cGAMP across the plasma membrane through LRRC8A-containing VRACs, feeding STING activation; real, but not required for every cGAMP-dependent process in vivo. Reason: Contested, and the dispute is about physiological requirement, not about the transport itself. Lahey et al. 2020 established VRAC as a widely expressed cGAMP transporter whose activity depends on subunit composition - promoted by LRRC8C/LRRC8E and suppressed by LRRC8D (PMID:33171122) - and two independent groups reported in vivo loss-of-function phenotypes consistent with it (Lrrc8e-deficient mice with impaired interferon responses to HSV-1, PMID:32277911; LRRC8C-dependent cGAMP uptake shaping T cell function, PMID:35105987). Thöne et al. 2026 is frequently read as refuting this, but it does not: in the same study, Lrrc8a disruption at endogenous expression showed that VRAC is the dominant plasma-membrane cGAMP transporter of MC38 cells, while tumour growth and the cGAMP-dependent antitumour response were nonetheless unaffected by loss of tumour- or host-expressed VRAC (PMID:41419196). A knockout showing that a physiological outcome proceeds without a protein does not show the protein cannot transport the substrate; it bounds the in vivo requirement. Consistent with that, the same authors accept a pivotal VRAC-dependent role after irradiation, and find B16-F10 cells barely use VRAC for cGAMP, i.e. the contribution is cell-type and context dependent. A 2025 study independently treats VRAC-mediated cGAMP transport as real and tunable, identifying PSA/NPEPPS as an inhibitory auxiliary subunit (PMID:41371222). Retained as a genuine molecular capability, but demoted from core: it is one permeant among many for a large-pore, broadly selective channel, it is a property of particular LRRC8A-containing heteromers rather than of LRRC8A as such, and its in vivo weight varies by cell type and stimulus. Supporting Evidence: PMID:41419196 We conclude that VRAC is the dominant PM cGAMP transporter of MC38 cells. PMID:41419196 However, tumor growth and the cGAMP-mediated antitumor immune response were independent of both tumor- and host-expressed VRAC. |
| GO:0005886 plasma membrane | EXP PMID:24782309 The protein synthesis inhibitor blasticidin s enters mammali... | ACCEPT | Summary: LRRC8A is a polytopic plasma-membrane protein; this is where the swelling-activated channel operates. Reason: Core location, supported by imaging, surface labelling and electrophysiology in multiple independent studies. Supporting Evidence: PMID:24782309 We characterize localization and topology of LRRC8A and LRRC8D and demonstrate that LRRC8D interacts with LRRC8A, LRRC8B, and LRRC8C. |
| GO:0005886 plasma membrane | EXP PMID:26824658 LRRC8 Proteins Form Volume-Regulated Anion Channels that Sen... | ACCEPT | Summary: LRRC8A is a polytopic plasma-membrane protein; this is where the swelling-activated channel operates. Reason: Core location, supported by imaging, surface labelling and electrophysiology in multiple independent studies. Supporting Evidence: PMID:24725410 SWELL1 is localized to the plasma membrane, and its knockdown dramatically reduces endogenous VRAC currents and regulatory cell volume decrease in various cell types. |
| GO:0001678 intracellular glucose homeostasis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: VRAC activity in insulin-target and beta cells influences glucose handling; transferred from mouse. Reason: Real but distal to the molecular function: a downstream organismal or tissue-level consequence of VRAC-mediated anion and osmolyte flux, transferred from the mouse or rat ortholog. Supporting Evidence: PMID:29371604 SWELL1 depletion in MIN6 cells and islets significantly impairs glucose-stimulated insulin secretion. |
| GO:0005225 volume-sensitive anion channel activity | IDA PMID:30095067 Structure of the human volume regulated anion channel. | ACCEPT | Summary: LRRC8A is the obligatory subunit of the volume-regulated anion channel; loss of LRRC8A ablates swelling-activated anion current in every cell type tested, and LRRC8A-containing hexamers reconstitute it. Reason: Core molecular function, established independently by two 2014 screens and confirmed by reconstitution, cryo-EM and structure-function analysis. Note that LRRC8A does not act alone in cells: VRAC currents are only restored when LRRC8A is co-expressed with LRRC8B-E, and subunit composition sets kinetics and substrate preference. Purified homohexameric LRRC8A nevertheless conducts anions in reconstituted systems, so the enables qualifier is defensible, but the physiological channel is a heteromer and this is recorded in core_functions with contributes_to plus in_complex. Supporting Evidence: PMID:30095067 SWELL1 (LRRC8A) is the only essential subunit of the Volume Regulated Anion Channel (VRAC), which regulates cellular volume homeostasis and is activated by hypotonic solutions. PMID:30095067 mutational analysis demonstrates that a charged residue at the narrowest constriction of the homomeric channel is an important pore determinant of heteromeric VRAC |
| GO:0005225 volume-sensitive anion channel activity | IDA PMID:33139539 LRRC8 family proteins within lysosomes regulate cellular osm... | ACCEPT | Summary: LRRC8A is the obligatory subunit of the volume-regulated anion channel; loss of LRRC8A ablates swelling-activated anion current in every cell type tested, and LRRC8A-containing hexamers reconstitute it. Reason: Core molecular function, established independently by two 2014 screens and confirmed by reconstitution, cryo-EM and structure-function analysis. Note that LRRC8A does not act alone in cells: VRAC currents are only restored when LRRC8A is co-expressed with LRRC8B-E, and subunit composition sets kinetics and substrate preference. Purified homohexameric LRRC8A nevertheless conducts anions in reconstituted systems, so the enables qualifier is defensible, but the physiological channel is a heteromer and this is recorded in core_functions with contributes_to plus in_complex. Supporting Evidence: PMID:33139539 LRRC8 family proteins on the plasma membrane play a critical role in cellular osmoregulation by forming volume-regulated anion channels (VRACs) necessary to prevent necrotic cell death. |
| GO:0005765 lysosomal membrane | IDA PMID:33139539 LRRC8 family proteins within lysosomes regulate cellular osm... | ACCEPT | Summary: A distinct intracellular pool of LRRC8 proteins on lysosomal membranes carries Lyso-VRAC currents. Reason: Genuine second site of action, demonstrated with a C-terminal di-leucine targeting mutant that removes Lyso-VRAC currents while leaving plasma-membrane VRAC intact. Supporting Evidence: PMID:33139539 LRRC8 proteins on lysosome membranes generate large lysosomal volume-regulated anion channel (Lyso-VRAC) currents in response to low cytoplasmic ionic strength conditions. PMID:33139539 We demonstrate that intracellular LRRC8 proteins acting within lysosomes also play an essential role in cellular osmoregulation. |
| GO:0005886 plasma membrane | IDA PMID:33139539 LRRC8 family proteins within lysosomes regulate cellular osm... | ACCEPT | Summary: LRRC8A is a polytopic plasma-membrane protein; this is where the swelling-activated channel operates. Reason: Core location, supported by imaging, surface labelling and electrophysiology in multiple independent studies. Supporting Evidence: PMID:33139539 LRRC8 family proteins on the plasma membrane play a critical role in cellular osmoregulation by forming volume-regulated anion channels (VRACs) necessary to prevent necrotic cell death. |
| GO:0006884 cell volume homeostasis | IDA PMID:33139539 LRRC8 family proteins within lysosomes regulate cellular osm... | ACCEPT | Summary: Regulatory volume decrease after hypotonic swelling requires LRRC8A. Reason: Core biological process: this is the physiological role the channel evolved to serve. Supporting Evidence: PMID:33139539 We demonstrate that intracellular LRRC8 proteins acting within lysosomes also play an essential role in cellular osmoregulation. |
| GO:0007283 spermatogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Spermatogenesis defect in the mouse ortholog, transferred by similarity. Reason: Real but distal to the molecular function: a downstream organismal or tissue-level consequence of VRAC-mediated anion and osmolyte flux, transferred from the mouse or rat ortholog. No human-specific evidence; kept because loss of an obligatory osmoregulatory channel plausibly impairs germ-cell development, but it is a tissue-level phenotype. |
| GO:0016020 membrane | IDA PMID:30095067 Structure of the human volume regulated anion channel. | MODIFY | Summary: Generic membrane localisation from a structural study and from a membrane-proteome survey. Reason: Not wrong, but uninformative: the specific compartments are known and already annotated. The plasma membrane is the site both sources actually sampled. Proposed replacements: plasma membrane Supporting Evidence: PMID:30095067 Here, we report a high-resolution cryo-electron microscopy structure of full-length human homo-hexameric SWELL1. |
| GO:0032024 positive regulation of insulin secretion | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: SWELL1-mediated swell-activated chloride current depolarises beta cells and supports glucose-stimulated insulin secretion. Reason: Real but distal to the molecular function: a downstream organismal or tissue-level consequence of VRAC-mediated anion and osmolyte flux, transferred from the mouse or rat ortholog. Supporting Evidence: PMID:29371604 we show that SWELL1 mediates a swell-activated, depolarizing chloride current PMID:29371604 SWELL1 depletion in MIN6 cells and islets significantly impairs glucose-stimulated insulin secretion. |
| GO:0034214 protein hexamerization | IDA PMID:30095067 Structure of the human volume regulated anion channel. | ACCEPT | Summary: LRRC8A forms a hexamer (homo-hexameric in the reported structures, hetero-hexameric in cells). Reason: Directly demonstrated by cryo-EM of full-length human LRRC8A and by size determination of native complexes; the hexameric assembly is what creates the conduction pathway. Supporting Evidence: PMID:30095067 Here, we report a high-resolution cryo-electron microscopy structure of full-length human homo-hexameric SWELL1. PMID:30095067 The structure reveals a trimer of dimers assembly with symmetry mismatch between the pore-forming domain and the cytosolic leucine-rich repeat (LRR) domains. |
| GO:0045663 positive regulation of myoblast differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Myoblast differentiation phenotype transferred from the mouse ortholog. Reason: Real but distal to the molecular function: a downstream organismal or tissue-level consequence of VRAC-mediated anion and osmolyte flux, transferred from the mouse or rat ortholog. |
| GO:0098656 monoatomic anion transmembrane transport | IDA PMID:30095067 Structure of the human volume regulated anion channel. | ACCEPT | Summary: Anion movement across the membrane is the direct consequence of VRAC opening. Reason: Core biological process, matching the molecular function. Supporting Evidence: PMID:30095067 SWELL1 (LRRC8A) is the only essential subunit of the Volume Regulated Anion Channel (VRAC), which regulates cellular volume homeostasis and is activated by hypotonic solutions. |
| GO:0140360 cyclic-GMP-AMP transmembrane transporter activity | IDA PMID:33171122 LRRC8A:C/E Heteromeric Channels Are Ubiquitous Transporters ... | KEEP AS NON CORE | Summary: VRAC channels containing LRRC8A together with LRRC8C or LRRC8E transport 2'3'-cGAMP; the activity is real but its physiological weight is disputed. Reason: Contested, and the dispute is about physiological requirement, not about the transport itself. Lahey et al. 2020 established VRAC as a widely expressed cGAMP transporter whose activity depends on subunit composition - promoted by LRRC8C/LRRC8E and suppressed by LRRC8D (PMID:33171122) - and two independent groups reported in vivo loss-of-function phenotypes consistent with it (Lrrc8e-deficient mice with impaired interferon responses to HSV-1, PMID:32277911; LRRC8C-dependent cGAMP uptake shaping T cell function, PMID:35105987). Thöne et al. 2026 is frequently read as refuting this, but it does not: in the same study, Lrrc8a disruption at endogenous expression showed that VRAC is the dominant plasma-membrane cGAMP transporter of MC38 cells, while tumour growth and the cGAMP-dependent antitumour response were nonetheless unaffected by loss of tumour- or host-expressed VRAC (PMID:41419196). A knockout showing that a physiological outcome proceeds without a protein does not show the protein cannot transport the substrate; it bounds the in vivo requirement. Consistent with that, the same authors accept a pivotal VRAC-dependent role after irradiation, and find B16-F10 cells barely use VRAC for cGAMP, i.e. the contribution is cell-type and context dependent. A 2025 study independently treats VRAC-mediated cGAMP transport as real and tunable, identifying PSA/NPEPPS as an inhibitory auxiliary subunit (PMID:41371222). Retained as a genuine molecular capability, but demoted from core: it is one permeant among many for a large-pore, broadly selective channel, it is a property of particular LRRC8A-containing heteromers rather than of LRRC8A as such, and its in vivo weight varies by cell type and stimulus. Supporting Evidence: PMID:33171122 Here, we identify LRRC8A heteromeric channels, better known as volume-regulated anion channels (VRAC), as widely expressed cGAMP transporters. PMID:33171122 LRRC8A forms complexes with LRRC8C and/or LRRC8E, depending on their expression levels, to transport cGAMP and other 2'3'-cyclic dinucleotides. PMID:33171122 In contrast, LRRC8D inhibits cGAMP transport. |
| GO:0140361 cyclic-GMP-AMP transmembrane import across plasma membrane | IDA PMID:33171122 LRRC8A:C/E Heteromeric Channels Are Ubiquitous Transporters ... | KEEP AS NON CORE | Summary: Import of extracellular cGAMP across the plasma membrane through LRRC8A-containing VRACs, feeding STING activation; real, but not required for every cGAMP-dependent process in vivo. Reason: Contested, and the dispute is about physiological requirement, not about the transport itself. Lahey et al. 2020 established VRAC as a widely expressed cGAMP transporter whose activity depends on subunit composition - promoted by LRRC8C/LRRC8E and suppressed by LRRC8D (PMID:33171122) - and two independent groups reported in vivo loss-of-function phenotypes consistent with it (Lrrc8e-deficient mice with impaired interferon responses to HSV-1, PMID:32277911; LRRC8C-dependent cGAMP uptake shaping T cell function, PMID:35105987). Thöne et al. 2026 is frequently read as refuting this, but it does not: in the same study, Lrrc8a disruption at endogenous expression showed that VRAC is the dominant plasma-membrane cGAMP transporter of MC38 cells, while tumour growth and the cGAMP-dependent antitumour response were nonetheless unaffected by loss of tumour- or host-expressed VRAC (PMID:41419196). A knockout showing that a physiological outcome proceeds without a protein does not show the protein cannot transport the substrate; it bounds the in vivo requirement. Consistent with that, the same authors accept a pivotal VRAC-dependent role after irradiation, and find B16-F10 cells barely use VRAC for cGAMP, i.e. the contribution is cell-type and context dependent. A 2025 study independently treats VRAC-mediated cGAMP transport as real and tunable, identifying PSA/NPEPPS as an inhibitory auxiliary subunit (PMID:41371222). Retained as a genuine molecular capability, but demoted from core: it is one permeant among many for a large-pore, broadly selective channel, it is a property of particular LRRC8A-containing heteromers rather than of LRRC8A as such, and its in vivo weight varies by cell type and stimulus. Supporting Evidence: PMID:33171122 We demonstrate that cGAMP is effluxed or influxed via LRRC8 channels, as dictated by the cGAMP electrochemical gradient. PMID:33171122 Here, we identify LRRC8A heteromeric channels, better known as volume-regulated anion channels (VRAC), as widely expressed cGAMP transporters. |
| GO:1902476 chloride transmembrane transport | IDA PMID:30095067 Structure of the human volume regulated anion channel. | ACCEPT | Summary: Chloride efflux through VRAC, the classical I(Cl,swell) current. Reason: Core biological process and more specific than the generic anion-transport terms carried by this gene. Supporting Evidence: PMID:29371604 we show that SWELL1 mediates a swell-activated, depolarizing chloride current |
| GO:0005225 volume-sensitive anion channel activity | ISS GO_REF:0000024 | ACCEPT | Summary: LRRC8A is the obligatory subunit of the volume-regulated anion channel; loss of LRRC8A ablates swelling-activated anion current in every cell type tested, and LRRC8A-containing hexamers reconstitute it. Reason: Core molecular function, established independently by two 2014 screens and confirmed by reconstitution, cryo-EM and structure-function analysis. Note that LRRC8A does not act alone in cells: VRAC currents are only restored when LRRC8A is co-expressed with LRRC8B-E, and subunit composition sets kinetics and substrate preference. Purified homohexameric LRRC8A nevertheless conducts anions in reconstituted systems, so the enables qualifier is defensible, but the physiological channel is a heteromer and this is recorded in core_functions with contributes_to plus in_complex. Supporting Evidence: PMID:24725410 We identified SWELL1 (LRRC8A), a member of a four-transmembrane protein family with unknown function, as essential for hypotonicity-induced iodide influx. PMID:24790029 Genomic disruption of LRRC8A ablated VRAC currents. |
| GO:0005225 volume-sensitive anion channel activity | IMP PMID:29769723 Structure of a volume-regulated anion channel of the LRRC8 f... | ACCEPT | Summary: LRRC8A is the obligatory subunit of the volume-regulated anion channel; loss of LRRC8A ablates swelling-activated anion current in every cell type tested, and LRRC8A-containing hexamers reconstitute it. Reason: Core molecular function, established independently by two 2014 screens and confirmed by reconstitution, cryo-EM and structure-function analysis. Note that LRRC8A does not act alone in cells: VRAC currents are only restored when LRRC8A is co-expressed with LRRC8B-E, and subunit composition sets kinetics and substrate preference. Purified homohexameric LRRC8A nevertheless conducts anions in reconstituted systems, so the enables qualifier is defensible, but the physiological channel is a heteromer and this is recorded in core_functions with contributes_to plus in_complex. Supporting Evidence: PMID:29769723 Here, using cryo-electron microscopy and X-ray crystallography, we determine the structure of a homomeric channel of the obligatory subunit LRRC8A. PMID:29769723 This protein conducts ions and has properties in common with endogenous heteromeric channels. |
| GO:0005886 plasma membrane | ISS GO_REF:0000024 | ACCEPT | Summary: LRRC8A is a polytopic plasma-membrane protein; this is where the swelling-activated channel operates. Reason: Core location, supported by imaging, surface labelling and electrophysiology in multiple independent studies. Supporting Evidence: PMID:24725410 SWELL1 is localized to the plasma membrane, and its knockdown dramatically reduces endogenous VRAC currents and regulatory cell volume decrease in various cell types. |
| GO:0034214 protein hexamerization | ISS GO_REF:0000024 | ACCEPT | Summary: LRRC8A forms a hexamer (homo-hexameric in the reported structures, hetero-hexameric in cells). Reason: Directly demonstrated by cryo-EM of full-length human LRRC8A and by size determination of native complexes; the hexameric assembly is what creates the conduction pathway. Supporting Evidence: PMID:26824658 we show that SWELL1 and up to four other LRRC8 subunits assemble into heterogeneous complexes of |
| GO:0098656 monoatomic anion transmembrane transport | ISS GO_REF:0000024 | ACCEPT | Summary: Anion movement across the membrane is the direct consequence of VRAC opening. Reason: Core biological process, matching the molecular function. Supporting Evidence: PMID:24725410 We identified SWELL1 (LRRC8A), a member of a four-transmembrane protein family with unknown function, as essential for hypotonicity-induced iodide influx. |
| GO:0098656 monoatomic anion transmembrane transport | IMP PMID:29769723 Structure of a volume-regulated anion channel of the LRRC8 f... | ACCEPT | Summary: Anion movement across the membrane is the direct consequence of VRAC opening. Reason: Core biological process, matching the molecular function. Supporting Evidence: PMID:29769723 This protein conducts ions and has properties in common with endogenous heteromeric channels. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-8941543 | ACCEPT | Summary: LRRC8A is a polytopic plasma-membrane protein; this is where the swelling-activated channel operates. Reason: Core location, supported by imaging, surface labelling and electrophysiology in multiple independent studies. Supporting Evidence: PMID:24725410 SWELL1 is localized to the plasma membrane, and its knockdown dramatically reduces endogenous VRAC currents and regulatory cell volume decrease in various cell types. |
| GO:0005225 volume-sensitive anion channel activity | IMP PMID:26824658 LRRC8 Proteins Form Volume-Regulated Anion Channels that Sen... | ACCEPT | Summary: LRRC8A is the obligatory subunit of the volume-regulated anion channel; loss of LRRC8A ablates swelling-activated anion current in every cell type tested, and LRRC8A-containing hexamers reconstitute it. Reason: Core molecular function, established independently by two 2014 screens and confirmed by reconstitution, cryo-EM and structure-function analysis. Note that LRRC8A does not act alone in cells: VRAC currents are only restored when LRRC8A is co-expressed with LRRC8B-E, and subunit composition sets kinetics and substrate preference. Purified homohexameric LRRC8A nevertheless conducts anions in reconstituted systems, so the enables qualifier is defensible, but the physiological channel is a heteromer and this is recorded in core_functions with contributes_to plus in_complex. Supporting Evidence: PMID:26824658 When reconstituted into bilayers, LRRC8 complexes are sufficient to form anion channels activated by osmolality gradients. PMID:26824658 These data demonstrate that LRRC8 proteins together constitute the VRAC pore and that hypotonic stress can activate VRAC through a decrease in cytoplasmic |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | MODIFY | Summary: Generic membrane localisation from a structural study and from a membrane-proteome survey. Reason: Not wrong, but uninformative: the specific compartments are known and already annotated. The plasma membrane is the site both sources actually sampled. Proposed replacements: plasma membrane |
| GO:0005253 monoatomic anion channel activity | IMP PMID:24725410 SWELL1, a plasma membrane protein, is an essential component... | MODIFY | Summary: Generic anion channel activity asserted with the contributes_to qualifier from the two founding loss-of-function studies. Reason: The qualifier is apt - LRRC8A contributes to a heteromeric channel rather than enabling the activity alone - but the term is the generic parent of the activity these same experiments actually established. The swelling-dependence is the informative part. Proposed replacements: volume-sensitive anion channel activity Supporting Evidence: PMID:24725410 point mutations in SWELL1 cause a significant change in VRAC anion selectivity, demonstrating that SWELL1 is an essential VRAC component |
| GO:0005253 monoatomic anion channel activity | IMP PMID:24790029 Identification of LRRC8 heteromers as an essential component... | MODIFY | Summary: Generic anion channel activity asserted with the contributes_to qualifier from the two founding loss-of-function studies. Reason: The qualifier is apt - LRRC8A contributes to a heteromeric channel rather than enabling the activity alone - but the term is the generic parent of the activity these same experiments actually established. The swelling-dependence is the informative part. Proposed replacements: volume-sensitive anion channel activity Supporting Evidence: PMID:24790029 Genomic disruption of LRRC8A ablated VRAC currents. PMID:24790029 Cells with disruption of all five LRRC8 genes required LRRC8A cotransfection with other LRRC8 isoforms to reconstitute VRAC currents. |
| GO:0005886 plasma membrane | IDA PMID:24725410 SWELL1, a plasma membrane protein, is an essential component... | ACCEPT | Summary: LRRC8A is a polytopic plasma-membrane protein; this is where the swelling-activated channel operates. Reason: Core location, supported by imaging, surface labelling and electrophysiology in multiple independent studies. Supporting Evidence: PMID:24725410 SWELL1 is localized to the plasma membrane, and its knockdown dramatically reduces endogenous VRAC currents and regulatory cell volume decrease in various cell types. |
| GO:0005886 plasma membrane | IDA PMID:24790029 Identification of LRRC8 heteromers as an essential component... | ACCEPT | Summary: LRRC8A is a polytopic plasma-membrane protein; this is where the swelling-activated channel operates. Reason: Core location, supported by imaging, surface labelling and electrophysiology in multiple independent studies. Supporting Evidence: PMID:24725410 SWELL1 is localized to the plasma membrane, and its knockdown dramatically reduces endogenous VRAC currents and regulatory cell volume decrease in various cell types. |
| GO:0006820 monoatomic anion transport | IMP PMID:24725410 SWELL1, a plasma membrane protein, is an essential component... | MODIFY | Summary: Anion transport asserted from LRRC8A knockdown/knockout in the two founding studies. Reason: Correct but too general for a channel: the movement is across a membrane, so the transmembrane term is the informative one, and the gene already carries it. Proposed replacements: monoatomic anion transmembrane transport Supporting Evidence: PMID:24725410 We identified SWELL1 (LRRC8A), a member of a four-transmembrane protein family with unknown function, as essential for hypotonicity-induced iodide influx. |
| GO:0006820 monoatomic anion transport | IMP PMID:24790029 Identification of LRRC8 heteromers as an essential component... | MODIFY | Summary: Anion transport asserted from LRRC8A knockdown/knockout in the two founding studies. Reason: Correct but too general for a channel: the movement is across a membrane, so the transmembrane term is the informative one, and the gene already carries it. Proposed replacements: monoatomic anion transmembrane transport Supporting Evidence: PMID:24790029 Genomic disruption of LRRC8A ablated VRAC currents. |
| GO:0006884 cell volume homeostasis | IMP PMID:24725410 SWELL1, a plasma membrane protein, is an essential component... | ACCEPT | Summary: Regulatory volume decrease after hypotonic swelling requires LRRC8A. Reason: Core biological process: this is the physiological role the channel evolved to serve. Supporting Evidence: PMID:24725410 SWELL1 is localized to the plasma membrane, and its knockdown dramatically reduces endogenous VRAC currents and regulatory cell volume decrease in various cell types. |
| GO:0006884 cell volume homeostasis | IMP PMID:24790029 Identification of LRRC8 heteromers as an essential component... | ACCEPT | Summary: Regulatory volume decrease after hypotonic swelling requires LRRC8A. Reason: Core biological process: this is the physiological role the channel evolved to serve. Supporting Evidence: PMID:24790029 Taurine flux and regulatory volume decrease also depended on LRRC8 proteins. |
| GO:0006970 response to osmotic stress | IMP PMID:24725410 SWELL1, a plasma membrane protein, is an essential component... | ACCEPT | Summary: VRAC is activated by osmotic swelling and by reduced cytoplasmic ionic strength. Reason: Core biological process; the stimulus that gates the channel. Supporting Evidence: PMID:24725410 We identified SWELL1 (LRRC8A), a member of a four-transmembrane protein family with unknown function, as essential for hypotonicity-induced iodide influx. |
| GO:0006970 response to osmotic stress | IMP PMID:24790029 Identification of LRRC8 heteromers as an essential component... | ACCEPT | Summary: VRAC is activated by osmotic swelling and by reduced cytoplasmic ionic strength. Reason: Core biological process; the stimulus that gates the channel. Supporting Evidence: PMID:24790029 Genomic disruption of LRRC8A ablated VRAC currents. |
| GO:0034702 monoatomic ion channel complex | IDA PMID:24790029 Identification of LRRC8 heteromers as an essential component... | ACCEPT | Summary: LRRC8A assembles into a hexameric ion channel complex with LRRC8B-E. Reason: Correct and central: the functional unit is the LRRC8 hexamer, confirmed biochemically and by cryo-EM. Supporting Evidence: PMID:24790029 LRRC8A formed heteromers with other LRRC8 multispan membrane proteins. PMID:24790029 Cells with disruption of all five LRRC8 genes required LRRC8A cotransfection with other LRRC8 isoforms to reconstitute VRAC currents. |
| GO:0009986 cell surface | IDA PMID:14660746 A congenital mutation of the novel gene LRRC8 causes agammag... | ACCEPT | Summary: Surface expression of LRRC8 on lymphocytes. Reason: Consistent with the plasma-membrane localisation; cell surface is correct though less informative than GO:0005886, which this gene also carries. Supporting Evidence: PMID:14660746 It is expressed on T cells as well as on B-lineage cells. |
| GO:0002329 pre-B cell differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: LRRC8A is required for the pro-B to pre-B cell transition; a truncating human allele causes agammaglobulinemia. Reason: Real but distal to the molecular function: a downstream organismal or tissue-level consequence of VRAC-mediated anion and osmolyte flux, transferred from the mouse or rat ortholog. Well documented for this gene in human and mouse, but it is a developmental requirement downstream of channel activity rather than the activity itself. Note that disrupting the non-obligatory LRRC8B-E subunits has no detectable effect on T or B cell development, which argues the phenotype tracks LRRC8A specifically. Supporting Evidence: PMID:14660746 These results indicate that LRRC8 is responsible for the B cell deficiency in this patient and is required for B cell development. PMID:41419196 Disruption of any of the non-essential subunits, LRRC8B-LRRC8E, had no discernible effect on T or B cell development in mice. |
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Download this section (compressed HTML)Q: Is VRAC-mediated cGAMP transport required for any cGAMP-dependent physiological process in vivo, or only permissive? Thöne et al. 2026 show the MC38 antitumour response proceeds without VRAC even though VRAC is the dominant plasma-membrane cGAMP transporter of those cells, while Lrrc8e and Lrrc8c mouse models show impaired antiviral interferon responses and altered T cell function. What distinguishes the settings where VRAC is dispensable from those where it is not?
Q: Should GO:0140360 be asserted on LRRC8A with enables, or with contributes_to? cGAMP permeation requires LRRC8C or LRRC8E and is suppressed by LRRC8D, so it is a property of particular heteromers rather than of LRRC8A alone.
Q: How should an obligatory pore-forming subunit that produces no current alone in cells but conducts as a homohexamer in reconstituted bilayers be represented - enables, contributes_to, or both under different conditions?
Q: Is the IBA is_active_in GO:0005737 cytoplasm annotation intended to capture the intracellular (lysosomal) VRAC pool? If so, GO:0005765 would state it far more usefully.
Q: Which of the rodent-derived organismal phenotypes (spermatogenesis, myoblast differentiation, glucose homeostasis) hold in human cells, and are any of them separable from the channel activity?
Experiment: Compare cGAMP flux and STING activation across a panel of primary human cell types in which LRRC8A is knocked out at endogenous expression, alongside quantification of LRRC8C, LRRC8D and LRRC8E transcript levels, to test whether the LRRC8C/E-to-LRRC8D ratio predicts how much of the flux is VRAC-dependent.
Experiment: Repeat the syngeneic tumour experiments of Thöne et al. with a tumour line that, unlike B16-F10, depends on VRAC for cGAMP uptake, and under conditions that raise extracellular cGAMP (irradiation, DNA virus infection), to test the authors' own proposal that VRAC matters only when extracellular cGAMP is high.
Experiment: Engineer a pore mutant of LRRC8A that selectively abolishes cGAMP permeation while sparing chloride conduction and regulatory volume decrease, and knock it in, to separate the immunological role from the osmoregulatory role in vivo.
Experiment: Determine whether reconstituted homohexameric LRRC8A shows osmolality-gated conduction with the same selectivity as native heteromeric VRAC, to settle whether enables or contributes_to is the correct qualifier for the molecular function.
Experiment: Test whether disrupting the SWELL1-PSA interface, rather than inhibiting PSA aminopeptidase activity, tunes cGAMP-dependent STING signalling in vivo, as proposed by Zheng et al.
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