Affinage

CLCC1

Chloride channel CLIC-like protein 1 · UniProt Q96S66

Round 2 corrected
Length
551 aa
Mass
62.0 kDa
Annotated
2026-04-28
40 papers in source corpus 9 papers cited in narrative 11 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CLCC1 is an ER-resident, pore-forming anion channel that maintains ER ion and Ca²⁺ homeostasis, ER morphology, protein-folding capacity, lipid bilayer symmetry, and nuclear envelope membrane fusion. It forms homomultimers whose channel activity is inhibited by luminal Ca²⁺ (via D25 and D181) and facilitated by PIP₂ (via K298), and it sustains steady-state [Cl⁻]ER, [K⁺]ER, and [Ca²⁺]ER; loss-of-function mutations cause ER stress, misfolded protein accumulation, and ALS-like motor neuron degeneration in conditional knockout mice (PMID:37142673), while a D25E variant impairs channel function and causes retinal degeneration in zebrafish and mice (PMID:30157172). CLCC1 partners with the phospholipid scramblase TMEM41B to promote trans-bilayer phospholipid equilibration at the ER, and its loss produces giant lumenal lipid droplets and accelerates metabolic-dysfunction-associated steatohepatitis (PMID:41741642). CLCC1 also functions as a membrane fusogen required for nuclear pore complex biogenesis and herpesviral nuclear egress, with loss causing nuclear membrane herniations and blebbing (PMID:41271665).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2015 High

    Establishing CLCC1 as essential for ER protein-folding homeostasis resolved the molecular basis of a progressive neurodegenerative phenotype in mice and linked the gene's loss to ER stress and ubiquitinated-protein accumulation.

    Evidence Positional cloning of a retrotransposon insertion in Clcc1 in a mouse model, supplemented by siRNA knockdown in cultured cells with GRP78 and ubiquitin readouts

    PMID:25698737

    Open questions at the time
    • Molecular mechanism (channel vs. other activity) was unknown
    • Whether CLCC1 loss in other tissues caused similar pathology was untested
    • Direct biochemical activity of the protein was not demonstrated
  2. 2018 High

    Demonstrating that CLCC1 functions as an intracellular chloride channel and that the disease-associated D25E variant impairs channel activity connected the ER-stress phenotype to a specific ion-conduction defect and extended pathology to the retina.

    Evidence Electrophysiology of CLCC1 channel function, siRNA knockdown-induced apoptosis in ARPE-19 cells, TALEN-knockout zebrafish with wild-type mRNA rescue, ERG recordings, heterozygous mouse retinal phenotyping

    PMID:30157172

    Open questions at the time
    • Whether CLCC1 itself forms the pore or requires auxiliary subunits was unresolved
    • Selectivity profile and gating mechanism were not fully characterized
    • Downstream signaling between ion flux and UPR induction was unclear
  3. 2019 Medium

    Identification of CLCC1 as an interactor of mitochondrial microprotein PIGBOS at ER–mitochondria contact sites placed the channel at inter-organelle signaling hubs involved in UPR regulation.

    Evidence BioID proximity labeling and co-localization microscopy at MAMs; UPR and cell death readouts upon PIGBOS loss

    PMID:31653868

    Open questions at the time
    • Functional consequence was shown via PIGBOS KO, not direct CLCC1 manipulation in this study
    • Whether CLCC1 channel activity is modulated at MAMs was not tested
    • Stoichiometry and directness of the CLCC1–PIGBOS interaction were not established
  4. 2023 High

    Direct electrophysiology of ER-derived vesicles established CLCC1 as a pore-forming homomultimeric anion channel gated by luminal Ca²⁺ (D25/D181) and PIP₂ (K298), and conditional knockout demonstrated cell-autonomous motor neuron loss with ALS-like features, unifying ion homeostasis and neurodegeneration.

    Evidence Patch-clamp of ER vesicles, site-directed mutagenesis, ion imaging for [Cl⁻]ER/[K⁺]ER/[Ca²⁺]ER, co-IP for homomultimerization, conditional Clcc1 KO mouse

    PMID:37142673

    Open questions at the time
    • High-resolution structure of the channel pore is lacking
    • Precise stoichiometry of the homomultimer is not defined
    • Causal link between specific ion imbalance (Cl⁻ vs. K⁺ vs. Ca²⁺) and neurodegeneration has not been dissected
  5. 2023 Medium

    Identification of SARS-CoV-2 ORF3A as a CLCC1 interactor that phenocopies CLCC1 knockdown-induced UPR suggested that viral proteins can co-opt or disrupt CLCC1-dependent ER homeostasis.

    Evidence Co-immunoprecipitation, co-localization, siRNA knockdown epistasis with ORF3A expression, UPR reporter and cell death assays

    PMID:37033725

    Open questions at the time
    • Direct effect of ORF3A on CLCC1 channel activity was not measured
    • Physiological relevance during live SARS-CoV-2 infection was not demonstrated
    • Mechanism of protection from ORF3A-mediated death upon CLCC1 knockdown is unclear
  6. 2024 Medium

    Proteomic mapping of the CLCC1 interactome confirmed its ER-centric interaction network, identified calnexin and SigmaR1 as novel partners (including at MAMs), and showed that the D25E pathogenic variant remodels the interactome.

    Evidence LC-MS interactome of wild-type and D25E CLCC1, co-localization microscopy for calnexin and SigmaR1

    PMID:38621504

    Open questions at the time
    • Interactions validated only by co-localization, not reciprocal co-IP
    • Functional consequences of altered interactome for the D25E variant were not tested
    • Whether calnexin or SigmaR1 modulate channel activity is unknown
  7. 2025 High

    A genome-wide CRISPR screen revealed that CLCC1 is required for herpesviral nuclear egress at the membrane fusion step, and its loss in uninfected cells causes nuclear blebbing, establishing CLCC1 as a host membrane fusogen with an ancient evolutionary role hijacked by herpesviruses.

    Evidence Whole-genome CRISPR screen, CLCC1 KO cells with viral titer and capsid localization assays, nuclear morphology imaging, phylogenetic analysis of viral CLCC1 homologs

    PMID:41271665

    Open questions at the time
    • Mechanism by which CLCC1 mediates membrane fusion is uncharacterized at the biochemical level
    • Whether the fusogenic activity depends on channel function is unknown
    • Relationship between nuclear blebbing phenotype and NPC biogenesis was not dissected in this study
  8. 2025 High

    Discovery that CLCC1 partners with TMEM41B to promote ER phospholipid scrambling and lipoprotein biogenesis revealed a lipid-homeostatic function; loss causes giant lumenal lipid droplets and accelerates steatohepatitis, linking CLCC1 to systemic metabolic disease.

    Evidence CRISPR KO in cells and mice, co-IP with TMEM41B, lipid droplet/ER morphology imaging, lipoprotein secretion assays, liver histopathology

    PMID:41741642

    Open questions at the time
    • Whether CLCC1 ion-channel activity is required for its scramblase-partnering role is not determined
    • Structural basis of the CLCC1–TMEM41B interaction is unknown
    • Relative contribution of lipid vs. ion homeostasis defects to liver pathology is unclear
  9. 2025 Medium

    Pharmacological targeting of CLCC1 by Senkyunolide A, which promotes CLCC1 ubiquitination and inhibits ER Ca²⁺ release, demonstrated that CLCC1 activity drives cholangiocyte proliferation in cholestatic liver disease, providing proof-of-concept for therapeutic modulation.

    Evidence SenA binding assay, ubiquitination assay, Ca²⁺ imaging, siRNA in primary cholangiocytes and human biliary epithelial cells, bile-duct-ligation mouse model

    PMID:40664817

    Open questions at the time
    • Direct binding site of SenA on CLCC1 relies on molecular docking and needs structural confirmation
    • Specificity of SenA for CLCC1 vs. off-target effects was not comprehensively assessed
    • Whether ubiquitination-mediated degradation or direct channel block is the primary inhibitory mechanism is unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include the high-resolution structure of the CLCC1 channel, whether ion-channel and membrane-fusion/scramblase-partnering activities are mechanistically separable, and how disruption of distinct CLCC1 functions (ion homeostasis, lipid scrambling, NPC assembly) leads to tissue-specific disease outcomes.
  • No high-resolution structure exists
  • Separation-of-function mutants distinguishing channel, fusogenic, and scramblase-partnering roles have not been generated
  • Tissue-specific phenotype determinants (neuronal vs. retinal vs. hepatic) are not understood

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005783 endoplasmic reticulum 5 GO:0005635 nuclear envelope 2
Pathway
GO:0005215 transporter activity 2 R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-382551 Transport of small molecules 2 R-HSA-8953897 Cellular responses to stimuli 2 R-HSA-1430728 Metabolism 1
Partners
CANXPIGBOSSIGMAR1TMEM41BTOR1A
Complex memberships
CLCC1 homomultimerCLCC1–TMEM41B complex

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 Loss-of-function mutation in Clcc1 (retrotransposon insertion) in mice causes progressive cerebellar granule cell death and peripheral motor axon degeneration. Acute knockdown of Clcc1 in cultured cells increases sensitivity to ER stress, GRP78 is upregulated in Clcc1-deficient neurons in vivo, and ubiquitinated proteins accumulate prior to neurodegeneration, establishing that CLCC1 is required for ER protein-folding homeostasis. Positional cloning, retrotransposon insertion mouse model, siRNA knockdown in cultured cells, immunohistochemistry for GRP78 and ubiquitinated proteins The Journal of neuroscience High 25698737
2018 CLCC1 functions as an intracellular chloride channel highly expressed in the retina; a missense variant p.D25E decreases CLCC1 channel function and causes mutant protein to accumulate in granules within the ER lumen. siRNA knockdown of CLCC1 induces apoptosis in ARPE-19 cells, and loss of CLCC1 in zebrafish impairs cone ERG response, retinal thickness, and opsin expression — all rescued by wild-type CLCC1 mRNA injection. Electrophysiology (channel function assay), immunofluorescence/EM for protein localization, siRNA knockdown, TALEN knockout zebrafish with rescue by mRNA injection, ERG recordings, Clcc1+/- mouse phenotyping PLoS genetics High 30157172
2019 CLCC1 interacts with the mitochondrial outer membrane microprotein PIGBOS at ER-mitochondria contact sites (MAMs). Loss of PIGBOS (the interacting partner) leads to heightened UPR and increased cell death, placing CLCC1 at the ER-mitochondria interface as part of inter-organelle UPR regulation. Co-localization microscopy, proximity interaction (BioID), functional loss-of-function studies of PIGBOS with UPR readouts Nature communications Medium 31653868
2023 CLCC1 is a pore-forming component of an ER anion channel that forms homomultimers. Channel activity is inhibited by luminal Ca2+ (binding mediated by conserved residues D25 and D181 in the N-terminus) and facilitated by PIP2 (sensed by K298 in the intraluminal loop). CLCC1 maintains steady-state [Cl-]ER, [K+]ER, and ER morphology, and regulates ER Ca2+ homeostasis including internal Ca2+ release and steady-state [Ca2+]ER. ALS-associated mutations increase steady-state [Cl-]ER and impair ER Ca2+ homeostasis. Conditional knockout of Clcc1 cell-autonomously causes motor neuron loss, ER stress, misfolded protein accumulation, and ALS-like pathologies. Electrophysiology (patch-clamp of ER-derived vesicles), site-directed mutagenesis of Ca2+-binding and PIP2-sensing residues, ion imaging ([Cl-]ER, [K+]ER, [Ca2+]ER), co-IP for homomultimerization, conditional Clcc1 knockout mouse, phenotypic comparison of multiple loss-of-function alleles Cell research High 37142673
2023 SARS-CoV-2 ORF3A co-localizes with and co-immunoprecipitates with CLCC1. ORF3A expression triggers a UPR similar to CLCC1 knockdown; cells with CLCC1 knockdown are partially protected from ORF3A-mediated cell death, and pre-upregulation of UPR targets (HSPA6, spliced XBP1) by CLCC1 knockdown prevents further induction by ORF3A, placing CLCC1 in the same pathway as ORF3A-induced UPR. Co-immunoprecipitation, co-localization microscopy, siRNA knockdown, transcriptional UPR reporter assays, cell death assays with chemical chaperone rescue PeerJ Medium 37033725
2024 The CLCC1 interactome (identified by LC-MS) is substantially composed of ER-localized proteins. The pathogenic p.Asp25Glu variant causes a notable loss and gain of specific protein interactors, with increased association with cytoplasmic proteins. Two novel interactors, Calnexin and SigmaR1, were validated by co-localization microscopy, and CLCC1 was shown to co-localize with SigmaR1 not only at the ER but also at mitochondria-associated ER membranes (MAMs). Liquid chromatography-mass spectrometry (LC-MS) interactome, co-localization microscopy Neuroscience letters Medium 38621504
2025 CLCC1 is required for the fusion stage of herpes simplex virus 1 nuclear egress (identified by whole-genome CRISPR screen). Loss of CLCC1 causes accumulation of capsid-containing perinuclear vesicles and a drop in viral titers. In uninfected cells, loss of CLCC1 causes nuclear blebbing, implicating CLCC1 in host nuclear envelope membrane fusion. Herpesviruses infecting mollusks and fish encode viral CLCC1 homologs acquired by horizontal gene transfer, suggesting CLCC1 mediates an ancient membrane fusion mechanism hijacked by herpesviruses. Whole-genome CRISPR screen, CLCC1 knockout cells with viral titer and capsid localization assays, nuclear morphology imaging, phylogenetic analysis Nature communications High 41271665
2025 CLCC1 regulates trans-bilayer equilibration of phospholipids at the ER by partnering with the phospholipid scramblase TMEM41B to recognize imbalanced ER bilayers and promote lipid scrambling. Loss of CLCC1 leads to emergence of giant lumenal lipid droplets enclosed by imbalanced ER bilayers and accelerates metabolic-dysfunction-associated liver steatohepatitis (MASH), establishing CLCC1 as a regulator of lipoprotein biogenesis and systemic lipid homeostasis. CRISPR-Cas9 knockout (cells and mice), co-immunoprecipitation/interaction with TMEM41B, lipid droplet and ER morphology imaging, lipoprotein secretion assays, liver steatosis pathology in mouse KO Nature High 41741642
2025 Senkyunolide A (SenA) binds CLCC1 and promotes its ubiquitination, thereby inhibiting CLCC1 activity and ER Ca2+ release in cholangiocytes. Inhibiting CLCC1 prevents Ca2+-mediated cholangiocyte proliferation and ductular reaction in cholestatic liver disease; si-CLCC1-loaded liposomes targeting cholangiocytes enhanced anti-ductular reaction effects. Molecular docking/binding assay (SenA-CLCC1 interaction), ubiquitination assay, siRNA knockdown, Ca2+ imaging, BDL animal model, primary cholangiocyte and human intrahepatic biliary epithelial cell experiments Acta pharmacologica Sinica Medium 40664817
2025 CLCC1 is identified as the human functional homolog of yeast Brl1p/Brr6p nuclear pore complex (NPC) assembly factors. Loss of CLCC1 in human cells causes extensive nuclear membrane herniations consistent with impaired NPC assembly. In Drosophila, loss of dClcc1 phenocopies Torsin-loss nuclear membrane fusion defects at NPC assembly sites; CLCC1/dClcc1 overexpression rescues NPC biogenesis and developmental defects caused by Torsin loss-of-function. Proximity labeling identified CLCC1 as a Torsin1A binding partner. Proximity labeling (BioTurboID), CRISPR-Cas9 KO in human cells, Drosophila genetic loss-of-function and rescue experiments, nuclear morphology EM/fluorescence imaging, remote homology/phylogenetic analysis bioRxiv (preprint)preprint Medium
2024 CRISPR-Cas9 chemical-genetic interaction screens identified CLCC1 as a critical regulator of hepatic neutral lipid flux. Loss of CLCC1 results in large lumenal ER lipid droplets with lipoprotein properties, and knockout in mice causes liver steatosis. Remote homology analysis identified a domain in CLCC1 homologous to yeast Brl1p/Brr6p, and loss of CLCC1 leads to extensive nuclear membrane herniations, consistent with impaired NPC assembly. Genome-wide CRISPR-Cas9 chemical-genetic screens, KO mouse liver histology, EM of ER lipid droplets, remote homology search, nuclear morphology analysis bioRxiv (preprint)preprint Medium

Source papers

Stage 0 corpus · 40 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature 3411 32353859
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2018 High-Density Proximity Mapping Reveals the Subcellular Organization of mRNA-Associated Granules and Bodies. Molecular cell 580 29395067
2020 Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms. Science (New York, N.Y.) 564 33060197
2021 Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV. Nature 532 33845483
2015 A Dynamic Protein Interaction Landscape of the Human Centrosome-Cilium Interface. Cell 433 26638075
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2012 Interpreting cancer genomes using systematic host network perturbations by tumour virus proteins. Nature 319 22810586
2010 Dynamics of cullin-RING ubiquitin ligase network revealed by systematic quantitative proteomics. Cell 318 21145461
2020 Virus-Host Interactome and Proteomic Survey Reveal Potential Virulence Factors Influencing SARS-CoV-2 Pathogenesis. Med (New York, N.Y.) 291 32838362
2017 Genome-wide CRISPR screen identifies HNRNPL as a prostate cancer dependency regulating RNA splicing. Proceedings of the National Academy of Sciences of the United States of America 282 28611215
2018 An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations. Nature communications 201 29568061
2020 Systems analysis of RhoGEF and RhoGAP regulatory proteins reveals spatially organized RAC1 signalling from integrin adhesions. Nature cell biology 194 32203420
2019 A protein-interaction network of interferon-stimulated genes extends the innate immune system landscape. Nature immunology 159 30833792
2019 Regulation of the ER stress response by a mitochondrial microprotein. Nature communications 159 31653868
2020 A High-Density Human Mitochondrial Proximity Interaction Network. Cell metabolism 148 32877691
2022 A comprehensive SARS-CoV-2-human protein-protein interactome reveals COVID-19 pathobiology and potential host therapeutic targets. Nature biotechnology 140 36217030
2019 Mapping the proximity interaction network of the Rho-family GTPases reveals signalling pathways and regulatory mechanisms. Nature cell biology 137 31871319
2017 The human cytoplasmic dynein interactome reveals novel activators of motility. eLife 118 28718761
2007 Toward a confocal subcellular atlas of the human proteome. Molecular & cellular proteomics : MCP 114 18029348
1998 Prediction of the coding sequences of unidentified human genes. XI. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA research : an international journal for rapid publication of reports on genes and genomes 103 9872452
2017 The interactome of metabolic enzyme carbonic anhydrase IX reveals novel roles in tumor cell migration and invadopodia/MMP14-mediated invasion. Oncogene 96 28692057
2015 Loss of Clcc1 results in ER stress, misfolded protein accumulation, and neurodegeneration. The Journal of neuroscience : the official journal of the Society for Neuroscience 35 25698737
2018 Mutation in the intracellular chloride channel CLCC1 associated with autosomal recessive retinitis pigmentosa. PLoS genetics 32 30157172
2023 Disruption of ER ion homeostasis maintained by an ER anion channel CLCC1 contributes to ALS-like pathologies. Cell research 24 37142673
2023 SARS-CoV-2 ORF3A interacts with the Clic-like chloride channel-1 (CLCC1) and triggers an unfolded protein response. PeerJ 4 37033725
2022 CLCC1 c. 75C>A Mutation in Pakistani Derived Retinitis Pigmentosa Families Likely Originated With a Single Founder Mutation 2,000-5,000 Years Ago. Frontiers in genetics 3 35391798
2025 Senkyunolide A ameliorates cholestatic liver fibrosis by controlling CLCC1-mediated endoplasmic reticulum Ca2+ release. Acta pharmacologica Sinica 2 40664817
2024 Unraveling the CLCC1 interactome: Impact of the Asp25Glu variant and its interaction with SigmaR1 at the Mitochondrial-Associated ER Membrane (MAM). Neuroscience letters 2 38621504
2023 Mutation and clinical analysis of the CLCC1 gene in amyotrophic lateral sclerosis patients from Central South China. Annals of clinical and translational neurology 2 37916886
2026 CLCC1 governs ER bilayer equilibration to maintain lipid homeostasis. Nature 1 41741642
2025 ER protein CLCC1 promotes nuclear envelope fusion in herpesviral and host processes. Nature communications 1 41271665