Affinage

LRRC8E

Volume-regulated anion channel subunit LRRC8E · UniProt Q6NSJ5

Length
796 aa
Mass
90.2 kDa
Annotated
2026-06-10
20 papers in source corpus 13 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LRRC8E is an accessory subunit of heteromeric LRRC8 volume-regulated anion channels (VRACs), assembling with the obligatory LRRC8A subunit to form channels with subunit-specific transport and gating properties (PMID:26530471, PMID:28833202). LRRC8A/E channels confer distinct functional signatures: they preferentially mediate swelling-activated efflux of charged organic osmolytes such as d-aspartate rather than uncharged osmolytes like taurine (PMID:28833202), and they transport cGAMP and 2'3'-cyclic dinucleotides across the plasma membrane, enabling cell-to-cell transfer of cGAMP and contributing to interferon-dependent anti-viral innate immunity, with Lrrc8e-deficient mice showing impaired responses to HSV-1 (PMID:32277911, PMID:33171122). The voltage-dependent inactivation kinetics and anion selectivity of LRRC8A/E channels are governed by conserved charged residues in the first extracellular loop (EL1), and EL1 of LRRC8E is required for channel activity (PMID:27325695, PMID:29853476). A defining feature of LRRC8A/E channels is their dramatic (>10-fold) activation by oxidation, opposite to the inhibition seen with LRRC8A/C and LRRC8A/D heteromers; this potentiation is mediated by oxidation of two intracellular cysteines, C424 and C448, which form a disulfide bond driving an activating conformational change (PMID:28841766, PMID:35861288). In vivo, LRRC8E localizes specifically to renal collecting duct intercalated cells, distinct from other VRAC subunits, and its deletion does not produce the proximal tubulopathy caused by loss of LRRC8A or LRRC8D (PMID:35777784).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2004 Low

    Established LRRC8E as a member of the LRRC8 family with a predicted leucine-rich-repeat architecture, defining the candidate before any functional role was known.

    Evidence Bioinformatic sequence analysis and predicted structural comparison

    PMID:15094057

    Open questions at the time
    • Computational prediction only with no functional assay
    • Transmembrane topology and channel role unresolved at this stage
  2. 2015 High

    Placed LRRC8E within heteromeric VRACs and showed subunit-specific substrate handling, since LRRC8E-containing channels did not mediate cisplatin uptake unlike LRRC8A/D channels.

    Evidence Genetic knockout/knockdown of individual subunits with radiotracer and drug uptake assays

    PMID:26530471

    Open questions at the time
    • Did not define which substrates LRRC8A/E channels do transport
    • Stoichiometry of LRRC8E in the hexamer not resolved
  3. 2016 High

    Mapped the structural determinants of LRRC8A/E gating and selectivity to conserved charged residues in EL1, explaining how LRRC8E shapes channel voltage-dependent inactivation and anion permeability.

    Evidence LRRC8C/LRRC8E chimeras, point mutagenesis and electrophysiology

    PMID:27325695

    Open questions at the time
    • Atomic structure of the EL1 region not determined
    • Did not address physiological substrates
  4. 2016 Medium

    Demonstrated that LRRC8A/D/E expression alone is insufficient to reconstitute channel function, indicating additional required factors and constraining minimal-reconstitution models.

    Evidence siRNA knockdown and overexpression in KCP-4 and C127 cells with current measurements

    PMID:27764579

    Open questions at the time
    • Identity of the additional required factor(s) unknown
    • Single lab and single method
  5. 2017 High

    Defined a functional specialization of LRRC8A/C/E channels in releasing charged organic osmolytes, distinguishing them from LRRC8A/D channels that release uncharged osmolytes.

    Evidence RNAi knockdown with radiotracer flux assays in primary rat astrocytes under hypoosmotic challenge

    PMID:28833202

    Open questions at the time
    • Did not resolve the structural basis for charge selectivity
    • In vivo relevance in brain not tested
  6. 2017 High

    Revealed redox as a subunit-specific gating input, with LRRC8A/E channels potentiated >10-fold by oxidation while LRRC8A/C and LRRC8A/D are inhibited, establishing LRRC8E as a ROS-sensing VRAC subunit.

    Evidence Electrophysiology on tagged heteromers with oxidant treatment and comparison to Jurkat endogenous currents

    PMID:28841766

    Open questions at the time
    • Molecular oxidation target not yet identified
    • Physiological oxidant source unclear
  7. 2018 High

    Showed EL1 of LRRC8E is essential for VRAC activity and that an LRRC8A intracellular sequence confers homomeric channel activity, dissecting the domains controlling assembly and permeation.

    Evidence Chimera and domain-swap experiments across LRRC8 subunits with electrophysiology

    PMID:29853476

    Open questions at the time
    • No structural model of the functional chimeras
    • Endogenous assembly stoichiometry not addressed
  8. 2020 High

    Identified cGAMP and cyclic dinucleotides as physiological substrates of LRRC8A/E channels and linked the subunit to anti-viral innate immunity in vivo, where Lrrc8e-deficient mice showed impaired interferon responses and HSV-1 immunity.

    Evidence Biochemical transport assays, electrophysiology and Lrrc8e-knockout mice with HSV-1 infection and IFN readouts

    PMID:32277911

    Open questions at the time
    • Directionality control across diverse cell contexts not fully mapped
    • Quantitative contribution relative to other transporters unresolved
  9. 2020 High

    Refined the cGAMP transport model by showing LRRC8A partners with LRRC8C and/or LRRC8E in an expression-dependent manner, with LRRC8D inhibitory, and that transport direction follows the electrochemical gradient.

    Evidence Genome-wide CRISPR screen with transport and electrophysiological assays in multiple human cell lines and primary cells

    PMID:33171122

    Open questions at the time
    • Mechanism by which LRRC8D antagonizes cGAMP transport unknown
    • Regulation of subunit composition in vivo unclear
  10. 2021 Medium

    Uncovered a tonic activation mechanism whereby a serum protein and plasma-membrane-localized cGAS, via PIP2, open LRRC8A/E channels under isotonic conditions to support cGAMP transport.

    Evidence cGAS genetic analyses, serum proteinase K/heat treatment, transport assays and membrane fractionation

    PMID:33827893

    Open questions at the time
    • PIP2 role lacks full reconstitution
    • Identity of the serum protein component not defined
  11. 2022 High

    Identified the molecular targets of redox activation as intracellular cysteines C424 and C448 in LRRC8E, whose disulfide formation drives the activating conformational change.

    Evidence Chimeric/concatemeric constructs, cysteine mutagenesis and electrophysiology with oxidants

    PMID:35861288

    Open questions at the time
    • Disulfide bond not directly visualized structurally
    • Endogenous physiological oxidation conditions not established
  12. 2022 High

    Established a distinct in vivo localization and renal role, with LRRC8E confined to collecting duct intercalated cells and its deletion sparing proximal tubule function unlike LRRC8A/D loss.

    Evidence Epitope-tagged knock-in mice for localization and constitutive knockout with histology, urine/serum analysis and metabolomics

    PMID:35777784

    Open questions at the time
    • Functional role within intercalated cells not defined
    • Substrate transported in this renal context unknown
  13. 2025 Medium

    Demonstrated that LRRC8E is dispensable for lymphocyte development and cGAMP-mediated anti-tumor immunity in vivo, narrowing the in vivo physiological contexts in which LRRC8E is non-redundant.

    Evidence Selective LRRC8 knockout mice with syngeneic tumor models, cytokine measurements and lymphocyte flow cytometry

    PMID:41419196

    Open questions at the time
    • Negative result for a single context; other in vivo roles not excluded
    • Single lab
    • Compensating transporters not fully identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • The physiological substrate and function of LRRC8E within renal intercalated cells, and the identity of the additional factors and serum components required for channel activation, remain unresolved.
  • Endogenous role in intercalated cells uncharacterized
  • Required cofactor for reconstitution unidentified
  • Structural basis of redox gating not directly resolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 4 GO:0140104 molecular carrier activity 2 GO:0140299 molecular sensor activity 2
Localization
GO:0005886 plasma membrane 3
Pathway
R-HSA-382551 Transport of small molecules 3 R-HSA-168256 Immune System 2 R-HSA-8953897 Cellular responses to stimuli 2
Partners
CGASLRRC8ALRRC8CLRRC8D
Complex memberships
LRRC8 volume-regulated anion channel (VRAC)

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 LRRC8E (FLJ23420) was identified as a member of the LRRC8 family, predicted to encode a protein with 16 extracellular leucine-rich repeats but lacking four transmembrane regions present in the other family members, suggesting a distinct structural configuration. Bioinformatic sequence analysis and predicted structural comparison FEBS letters Low 15094057
2015 LRRC8E is a subunit of heteromeric LRRC8 volume-regulated anion channels (VRACs); however, LRRC8E-containing (but not LRRC8D-containing) VRACs do not contribute significantly to cisplatin uptake under isotonic conditions, whereas LRRC8A/LRRC8D channels are the primary mediators of cisplatin transport. Genetic knockout/knockdown of individual LRRC8 subunits combined with radiotracer and drug uptake assays The EMBO journal High 26530471
2016 The C-terminal part of the first extracellular loop (EL1) of LRRC8E, specifically two conserved charged residues equivalent to Lys-98 and Asp-100 in LRRC8A, determines voltage-dependent inactivation kinetics and contributes to iodide/chloride selectivity of LRRC8A/E heteromeric VRACs. Chimera construction between LRRC8C and LRRC8E, point mutagenesis, electrophysiology The Journal of biological chemistry High 27325695
2016 Overexpression of LRRC8A alone or together with LRRC8D or LRRC8E in VSOR-deficient KCP-4 cells failed to restore VSOR activity, indicating that LRRC8A/D/E expression alone is not sufficient for channel function and that additional unidentified factors are required. siRNA knockdown and overexpression in KCP-4 and C127 cells with electrophysiological current measurements Channels (Austin, Tex.) Medium 27764579
2017 In primary rat astrocytes, LRRC8A/C/E-containing heteromeric VRACs preferentially mediate swelling-activated release of charged organic osmolytes (d-aspartate), while LRRC8A/D channels dominate release of uncharged osmolytes (taurine, myo-inositol). Knockdown of LRRC8C+LRRC8E selectively reduced d-aspartate efflux without major effect on taurine release. RNAi knockdown of individual LRRC8 subunits combined with radiotracer flux assays in primary rat astrocytes under hypoosmotic challenge The Journal of physiology High 28833202
2017 LRRC8A/LRRC8E heteromeric channels are dramatically activated (>10-fold potentiation) by oxidation of intracellular cysteine residues via chloramine-T or tert-butyl hydroperoxide, in contrast to LRRC8A/LRRC8C and LRRC8A/LRRC8D heteromers which are inhibited by oxidation, demonstrating direct subunit-dependent modulation of VRAC by reactive oxygen species. Electrophysiology on fluorescently-tagged LRRC8 heteromers expressed in cells, oxidant treatment, comparison with Jurkat T lymphocyte endogenous currents The Journal of physiology High 28841766
2018 The first extracellular loop (EL1) connecting transmembrane domains 1 and 2 of LRRC8E is essential for VRAC activity. Replacing EL1 of LRRC8A with that of LRRC8E in a chimeric construct generates homomeric VRACs with normal volume-dependent regulation. A 25-amino acid sequence unique to the LRRC8A intracellular loop, when inserted into LRRC8E, is sufficient to generate homomeric VRAC activity, and influences anion permeability, rectification, and voltage sensitivity. Chimera construction and domain-swap experiments between LRRC8A, LRRC8C, LRRC8D, and LRRC8E; electrophysiology The Journal of general physiology High 29853476
2020 LRRC8A/LRRC8E-containing VRACs transport cGAMP and cyclic dinucleotides across the plasma membrane, mediating cell-to-cell transfer of cGAMP. Lrrc8e−/− mice exhibited impaired interferon responses and compromised immunity to HSV-1, establishing LRRC8E as a functionally important subunit for cGAMP transport and anti-viral innate immunity. Biochemical transport assays, electrophysiology, genetic knockout mice (Lrrc8e−/−), viral infection assays (HSV-1), IFN response measurement Immunity High 32277911
2020 LRRC8A forms complexes with LRRC8C and/or LRRC8E depending on their expression levels to transport cGAMP and other 2'3'-cyclic dinucleotides; in contrast, LRRC8D inhibits cGAMP transport. cGAMP is effluxed or influxed via LRRC8 channels depending on the electrochemical gradient. LRRC8A/C/E channels are key cGAMP transporters in resting primary human vasculature cells and universal human cGAMP transporters when activated. Genome-wide CRISPR screen, genetic knockout/overexpression, transport assays, electrophysiology in multiple human cell lines and primary cells Molecular cell High 33171122
2021 LRRC8A/E-containing VRACs specialized in cGAMP transport can be opened by a protein component in serum under resting (isotonic) conditions; serum depletion ablates tonic LRRC8A/E VRAC activity and decreases cGAMP transport. The plasma membrane-localized form of cGAS (not its DNA-binding or enzymatic activity) enables VRAC activation, and phospholipid PIP2 is instrumental in membrane localization of cGAS and its association with VRACs. Genetic analyses (cGAS knockouts/mutants), proteinase K and heat treatment of serum, cGAMP transport assays, membrane fractionation Journal of immunology Medium 33827893
2022 Two intracellular cysteines in the first two leucine-rich repeats of LRRC8E (C424 and C448) are the molecular targets of oxidation. Oxidation likely forms a disulfide bond between these two cysteines, inducing a conformational change that activates LRRC8A/LRRC8E heteromeric channels. Chimeric and concatemeric LRRC8 constructs, site-directed mutagenesis of specific cysteines, electrophysiology with oxidant treatment The Journal of physiology High 35861288
2022 In the kidney, LRRC8E localizes specifically to intercalated cells of the collecting duct, a distinct localization from other VRAC subunits (LRRC8A, LRRC8B, LRRC8D in basolateral membranes of proximal tubules; LRRC8C exclusively in vascular endothelium). Constitutive deletion of Lrrc8e did not cause proximal tubulopathy (unlike Lrrc8d or Lrrc8a deletion), suggesting LRRC8E plays a distinct renal role. Epitope-tagged knock-in mice for localization, constitutive knockout mice with histology and urine/serum functional analysis, metabolomics Journal of the American Society of Nephrology High 35777784
2025 Disruption of LRRC8E (along with LRRC8B, LRRC8C, or LRRC8D) had no discernible effect on T or B cell development in mice. In subcutaneous tumor models, disruption of LRRC8E in host cells did not impair the cGAMP-mediated anti-tumor immune response, indicating that VRAC-mediated cGAMP transport involving LRRC8E is dispensable for anti-tumor immunity in vivo, which is instead primarily mediated by other transporters. Genetic knockout mice with selective LRRC8 subunit disruptions, syngeneic subcutaneous tumor models (MC38, B16-F10), serum cytokine measurements, tumor growth assays, flow cytometry of lymphocyte development The Journal of biological chemistry Medium 41419196

Source papers

Stage 0 corpus · 20 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 Transfer of cGAMP into Bystander Cells via LRRC8 Volume-Regulated Anion Channels Augments STING-Mediated Interferon Responses and Anti-viral Immunity. Immunity 244 32277911
2015 Subunit composition of VRAC channels determines substrate specificity and cellular resistance to Pt-based anti-cancer drugs. The EMBO journal 225 26530471
2020 LRRC8A:C/E Heteromeric Channels Are Ubiquitous Transporters of cGAMP. Molecular cell 155 33171122
2017 Molecular composition and heterogeneity of the LRRC8-containing swelling-activated osmolyte channels in primary rat astrocytes. The Journal of physiology 85 28833202
2016 Inactivation and Anion Selectivity of Volume-regulated Anion Channels (VRACs) Depend on C-terminal Residues of the First Extracellular Loop. The Journal of biological chemistry 50 27325695
2017 Subunit-dependent oxidative stress sensitivity of LRRC8 volume-regulated anion channels. The Journal of physiology 48 28841766
2004 LRRC8 involved in B cell development belongs to a novel family of leucine-rich repeat proteins. FEBS letters 47 15094057
2019 LINC00958 facilitates cervical cancer cell proliferation and metastasis by sponging miR-625-5p to upregulate LRRC8E expression. Journal of cellular biochemistry 44 31691355
2018 Intracellular and extracellular loops of LRRC8 are essential for volume-regulated anion channel function. The Journal of general physiology 39 29853476
2016 Specific and essential but not sufficient roles of LRRC8A in the activity of volume-sensitive outwardly rectifying anion channel (VSOR). Channels (Austin, Tex.) 33 27764579
2017 Leucine-rich repeat-containing 8B protein is associated with the endoplasmic reticulum Ca2+ leak in HEK293 cells. Journal of cell science 25 28972132
2022 Renal Deletion of LRRC8/VRAC Channels Induces Proximal Tubulopathy. Journal of the American Society of Nephrology : JASN 20 35777784
2021 Regulation of Anion Channel LRRC8 Volume-Regulated Anion Channels in Transport of 2'3'-Cyclic GMP-AMP and Cisplatin under Steady State and Inflammation. Journal of immunology (Baltimore, Md. : 1950) 20 33827893
2022 Molecular determinants underlying volume-regulated anion channel subunit-dependent oxidation sensitivity. The Journal of physiology 18 35861288
2014 A simple method for estimating the strength of natural selection on overlapping genes. Genome biology and evolution 16 25552532
2022 LncRNA PCAT6 activated by SP1 facilitates the progression of breast cancer by the miR-326/LRRC8E axis. Anti-cancer drugs 8 34620745
2022 Knockdown of LINC00511 decreased cisplatin resistance in non-small cell lung cancer by elevating miR-625 level to suppress the expression of leucine rich repeat containing eight volume-regulated anion channel subunit E. Human & experimental toxicology 7 35363093
2016 Association between genes on chromosome 19p13.2 and panic disorder. Psychiatric genetics 7 27610895
2024 Unveiling the therapeutic potential: KBU2046 halts triple-negative breast cancer cell migration by constricting TGF-β1 activation in vitro. Oncology research 3 39449805
2025 A protective cGAMP-mediated anti-tumor immune response can proceed without LRRC8/VRAC channels. The Journal of biological chemistry 0 41419196

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