Affinage

COPZ1

Coatomer subunit zeta-1 · UniProt P61923

Round 2 corrected
Length
177 aa
Mass
20.2 kDa
Annotated
2026-04-28
65 papers in source corpus 8 papers cited in narrative 8 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

COPZ1 is a subunit of the heptameric COPI coatomer complex essential for retrograde Golgi-to-ER vesicle trafficking, whose loss collapses Golgi architecture and triggers multiple cell-death and stress pathways. COPZ1 depletion causes abortive autophagy, ER stress/unfolded protein response, and apoptosis selectively in tumor cells that have epigenetically silenced the paralog COPZ2; re-expression of COPZ2 rescues viability, demonstrating functional redundancy between the two zeta isoforms (PMID:21746916, PMID:28951131). COPZ1 directly binds NCOA4, and its loss promotes NCOA4-mediated ferritinophagy, elevating intracellular Fe²⁺, reactive oxygen species, and lipid peroxidation to induce ferroptosis, while also activating type I interferon/viral mimicry signaling and immunogenic cell death (PMID:33420375, PMID:39181476, PMID:32061953). Autosomal recessive loss-of-function mutations in COPZ1 cause severe congenital neutropenia in humans by impairing JAK/STAT/G-CSFR–dependent granulopoiesis and activating STING/interferon-stimulated gene pathways, a phenotype rescuable by COPZ2 transduction or HIF1α stabilization (PMID:39642330).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 2011 High

    Establishing that COPZ1 is essential for Golgi integrity and tumor cell survival, and that epigenetic silencing of the paralog COPZ2 in cancers creates a synthetic-lethal dependence on COPZ1, answered the question of why a ubiquitous vesicle-trafficking subunit could serve as a tumor-selective vulnerability.

    Evidence siRNA/shRNA knockdown across multiple tumor and normal cell lines, Golgi imaging, COPZ2 re-expression rescue, in vivo xenograft

    PMID:21746916

    Open questions at the time
    • Molecular mechanism linking Golgi collapse to selective apoptosis was unclear
    • Whether COPZ1 loss activates specific death pathways beyond general trafficking disruption was not resolved
    • No direct protein interaction partners mediating cell death were identified
  2. 2017 High

    Demonstrating that COPZ1 depletion triggers abortive autophagy, ER stress, and UPR activation specified the proximal stress pathways downstream of COPI dysfunction that mediate tumor cell killing.

    Evidence siRNA knockdown in thyroid tumor cells, western blot for autophagy/ER stress/UPR markers, in vivo xenograft siRNA treatment

    PMID:28951131

    Open questions at the time
    • Whether ER stress and autophagy block are parallel or sequential was not determined
    • The contribution of immunogenic signaling was not yet explored
  3. 2020 Medium

    Revealing that COPZ1 loss activates type I interferon/viral mimicry responses and induces immunogenic cell death — with DAMP release, dendritic cell maturation, and cytotoxic T cell priming — extended the consequences of COPZ1 depletion beyond cell-intrinsic death to anti-tumor immune activation.

    Evidence siRNA knockdown, secretome proteomics, dendritic cell co-culture and T cell proliferation/cytotoxicity assays

    PMID:32061953

    Open questions at the time
    • Single-laboratory finding without independent replication
    • The molecular trigger linking COPI disruption to type I IFN pathway activation was not identified
    • In vivo immune-mediated tumor rejection was not demonstrated
  4. 2021 High

    Identification of the COPZ1/NCOA4/FTH1 axis established that COPZ1 loss induces ferroptosis through NCOA4-dependent ferritinophagy, providing a specific iron-metabolism mechanism for tumor cell death beyond general trafficking failure.

    Evidence siRNA/shRNA knockdown in glioblastoma cells, NCOA4/FTH1 western blot, intracellular Fe²⁺ measurement, ferroptosis assays, in vivo xenograft

    PMID:33420375

    Open questions at the time
    • Direct physical interaction between COPZ1 and NCOA4 was not yet shown
    • Whether the ferroptosis axis operates in non-GBM tumor types was untested
  5. 2022 Medium

    Showing that BMI1 transcriptionally activates COPZ1 by binding its promoter placed COPZ1 expression under Polycomb-group regulation and linked oncogenic BMI1 signaling to COPI-dependent autophagy and proliferation.

    Evidence ChIP and luciferase reporter for promoter binding, BMI1 overexpression rescue of COPZ1-knockdown phenotype in breast cancer cells

    PMID:35789980

    Open questions at the time
    • Single-laboratory finding; BMI1-COPZ1 axis not confirmed in other tissue contexts
    • Whether BMI1 regulation of COPZ1 contributes to COPZ2 silencing in tumors was not addressed
  6. 2024 High

    Demonstrating direct physical binding between COPZ1 and NCOA4, and showing epistatic rescue by NCOA4 knockdown, confirmed that the COPZ1–NCOA4 interaction is the mechanistic node controlling ferritinophagy-driven ferroptosis upon COPZ1 loss.

    Evidence Co-immunoprecipitation for direct binding, double-knockdown epistasis, lysosome fractionation, lipid peroxidation and mitochondrial morphology assays in lung adenocarcinoma, xenograft model

    PMID:39181476

    Open questions at the time
    • Structural basis of the COPZ1–NCOA4 interaction (binding domain, stoichiometry) is unknown
    • Whether COPZ1 regulates NCOA4 via trafficking or by direct sequestration remains unresolved
  7. 2025 High

    Discovery that biallelic COPZ1 loss-of-function mutations cause severe congenital neutropenia established a human Mendelian disease, revealed that COPZ1-dependent COPI transport is essential for JAK/STAT/G-CSFR granulopoietic signaling, and showed that STING/ISG activation and ROS accumulation are cell-intrinsic consequences of COPZ1 deficiency in hematopoietic progenitors.

    Evidence Patient genetics (truncating and missense mutations), human fibroblast retrograde transport assay, CD34⁺ differentiation assays, zebrafish myelopoiesis model, pharmacological rescue (IOX2) and COPZ2 lentiviral rescue

    PMID:39642330

    Open questions at the time
    • How impaired retrograde transport specifically disrupts G-CSFR surface expression or JAK/STAT activation is not molecularly detailed
    • Whether the NCOA4/ferroptosis axis contributes to neutropenia pathogenesis was not examined
    • Long-term clinical outcomes of COPZ1-deficient patients remain unreported

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis of the COPZ1–NCOA4 interaction, the precise mechanism linking COPI retrograde transport failure to STING/type I IFN activation, and whether COPZ1 regulates NCOA4 through trafficking versus direct sequestration remain unresolved.
  • No crystal structure or cryo-EM model of COPZ1 in complex with NCOA4 or within COPI
  • Mechanism connecting COPI disruption to cytosolic DNA sensing/STING is undefined
  • Relative contributions of ferroptosis, apoptosis, and immunogenic cell death in different tissue contexts are unquantified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 2 GO:0060090 molecular adaptor activity 2
Localization
GO:0005794 Golgi apparatus 3 GO:0031410 cytoplasmic vesicle 2 GO:0005829 cytosol 1
Pathway
R-HSA-5357801 Programmed Cell Death 4 R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-9612973 Autophagy 3 R-HSA-1643685 Disease 2 R-HSA-168256 Immune System 2
Partners
BMI1COPG1COPZ2FTH1NCOA4
Complex memberships
COPI coatomer

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 COPZ1 encodes a subunit of the COPI complex required for intracellular vesicle trafficking; its knockdown causes Golgi apparatus collapse, blocks autophagy, and induces apoptosis selectively in tumor cells. Tumor-specific silencing of the paralog COPZ2 creates synthetic dependence on COPZ1, and re-expression of COPZ2 rescues tumor cells from COPZ1 knockdown-induced death, demonstrating functional redundancy between the two isoforms. siRNA knockdown, shRNA stable expression, Golgi morphology imaging, cell viability/apoptosis assays, COPZ2 re-expression rescue experiments Proceedings of the National Academy of Sciences of the United States of America High 21746916
2017 siRNA-mediated COPZ1 depletion in thyroid tumor cells causes abortive autophagy, endoplasmic reticulum (ER) stress, unfolded protein response (UPR), and apoptosis, and reduces tumor growth in mouse xenograft models treated locally with COPZ1-targeting siRNA. siRNA knockdown, western blot for autophagy/ER stress/UPR markers, apoptosis assays, in vivo xenograft siRNA treatment Cancer letters High 28951131
2020 COPZ1 depletion in thyroid tumor cell lines activates the type I interferon (IFN) pathway and viral mimicry responses. The secretome from COPZ1-depleted cells is enriched for inflammatory molecules and damage-associated molecular patterns (DAMPs), induces dendritic cell maturation, and stimulates naïve T cell proliferation with increased cytotoxic activity against parental tumor cells, establishing an immunogenic cell death mechanism downstream of COPZ1 loss. siRNA knockdown, proteomic/secretome analysis, dendritic cell co-culture assays, T cell proliferation and cytotoxicity assays, pathway analysis Cancer letters Medium 32061953
2021 COPZ1 knockdown in glioblastoma cells increases nuclear receptor coactivator 4 (NCOA4) levels, leading to ferritin degradation (ferritinophagy), elevated intracellular ferrous iron (Fe2+), and ultimately ferroptosis. The COPZ1/NCOA4/FTH1 axis was identified as a critical mediator of iron metabolism in GBM, and COPZ1 shRNA reduced tumor growth ~60% in vivo. siRNA/shRNA knockdown, western blot for NCOA4/FTH1, intracellular Fe2+ measurement, ferroptosis assays, in vivo xenograft model Oncogene High 33420375
2022 BMI1 transcriptionally activates COPZ1 by binding to its promoter, as demonstrated by luciferase reporter assay and chromatin immunoprecipitation (ChIP). BMI1 overexpression reverses the inhibitory effects of COPZ1 knockdown on breast cancer cell proliferation and autophagy, placing COPZ1 downstream of the BMI1 transcriptional program. Luciferase reporter assay, ChIP, siRNA knockdown, BMI1 overexpression rescue, western blot for proliferation/apoptosis/autophagy markers Clinical & translational oncology Medium 35789980
2024 COPZ1 directly binds NCOA4, and COPZ1 knockdown in lung adenocarcinoma cells promotes NCOA4-mediated ferritinophagy by causing translocation of ferritin to lysosomes for degradation, elevating ROS and Fe2+, inducing lipid peroxidation and mitochondrial shrinkage. NCOA4 knockdown reverses the iron metabolism dysregulation caused by COPZ1 loss, confirming the COPZ1–NCOA4 interaction as mechanistically central. Co-immunoprecipitation (direct binding), siRNA double-knockdown epistasis, lysosome fractionation, lipid peroxidation assays, mitochondrial morphology imaging, xenograft model Biochimica et biophysica acta. General subjects High 39181476
2025 Autosomal recessive loss-of-function mutations in COPZ1 (truncating stop-codon and missense) cause severe congenital neutropenia in humans. The truncated COPZ1 protein shows predicted diminished interaction with COPI complex partner COPG1. Human fibroblasts carrying truncated COPZ1 display a block in retrograde protein transport from the Golgi to the ER. CD34+ hematopoietic cells with COPZ1 mutations have impaired granulocytic differentiation. Mechanistically, truncated COPZ1 downregulates JAK/STAT/CEBPE/G-CSFR signaling and hypoxia-responsive pathways while inducing STING and interferon-stimulated genes and increasing ROS. Granulopoiesis is restored by HIF1α stabilizer IOX2 or COPZ2 transduction. Patient genetics, human fibroblast retrograde transport assay, CD34+ cell differentiation assays, zebrafish myelopoiesis model, western blot/pathway analysis, pharmacological rescue, COPZ2 lentiviral transduction rescue Blood High 39642330
2025 Knockdown of COPZ1 (among five other COPI subunits) in Huh-7 hepatocarcinoma cells decreases HDL holoparticle uptake, reduces cell-surface abundance of scavenger receptor SR-BI (by interfering with its glycosylation), decreases apoA-I secretion, and increases ABCA1 cell-surface abundance and cholesterol efflux, placing COPZ1/COPI function upstream of SR-BI glycosylation and HDL metabolism in hepatocytes. Genome-wide RNAi screen, targeted siRNA knockdown, fluorescent HDL uptake assay, flow cytometry for SR-BI/ABCA1 surface abundance, apoA-I secretion measurement bioRxivpreprint Medium bio_10.1101_2025.08.21.25332476

Source papers

Stage 0 corpus · 65 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
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
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
1996 Coat proteins and vesicle budding. Science (New York, N.Y.) 789 8599108
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2012 A census of human soluble protein complexes. Cell 689 22939629
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
1994 Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. Gene 492 8125298
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
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
2010 Systematic analysis of human protein complexes identifies chromosome segregation proteins. Science (New York, N.Y.) 421 20360068
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2000 Identification of novel human genes evolutionarily conserved in Caenorhabditis elegans by comparative proteomics. Genome research 392 10810093
2000 Secretory protein trafficking and organelle dynamics in living cells. Annual review of cell and developmental biology 380 11031247
2011 New gene functions in megakaryopoiesis and platelet formation. Nature 332 22139419
2014 A quantitative chaperone interaction network reveals the architecture of cellular protein homeostasis pathways. Cell 325 25036637
1998 gp25L/emp24/p24 protein family members of the cis-Golgi network bind both COP I and II coatomer. The Journal of cell biology 294 9472029
1995 The ARF1 GTPase-activating protein: zinc finger motif and Golgi complex localization. Science (New York, N.Y.) 294 8533093
2012 A high-throughput approach for measuring temporal changes in the interactome. Nature methods 273 22863883
2022 Tau interactome maps synaptic and mitochondrial processes associated with neurodegeneration. Cell 256 35063084
2007 hORFeome v3.1: a resource of human open reading frames representing over 10,000 human genes. Genomics 222 17207965
2016 An organelle-specific protein landscape identifies novel diseases and molecular mechanisms. Nature communications 211 27173435
2015 A deep proteomics perspective on CRM1-mediated nuclear export and nucleocytoplasmic partitioning. eLife 198 26673895
2000 The debate about transport in the Golgi--two sides of the same coin? Cell 187 11030615
2000 Cloning and functional analysis of cDNAs with open reading frames for 300 previously undefined genes expressed in CD34+ hematopoietic stem/progenitor cells. Genome research 161 11042152
2021 Loss of COPZ1 induces NCOA4 mediated autophagy and ferroptosis in glioblastoma cell lines. Oncogene 147 33420375
2003 ER-to-Golgi transport: COP I and COP II function (Review). Molecular membrane biology 136 12893528
2017 RNA-binding activity of TRIM25 is mediated by its PRY/SPRY domain and is required for ubiquitination. BMC biology 135 29117863
2011 Interactions of pathological hallmark proteins: tubulin polymerization promoting protein/p25, beta-amyloid, and alpha-synuclein. The Journal of biological chemistry 131 21832049
1999 The Enterococcus hirae copper chaperone CopZ delivers copper(I) to the CopY repressor. FEBS letters 125 10069368
1999 NMR structure and metal interactions of the CopZ copper chaperone. The Journal of biological chemistry 103 10428839
2002 Copper transfer from the Cu(I) chaperone, CopZ, to the repressor, Zn(II)CopY: metal coordination environments and protein interactions. Biochemistry 100 11980486
2001 Copper trafficking: the solution structure of Bacillus subtilis CopZ. Biochemistry 99 11747441
2003 CopZ from Bacillus subtilis interacts in vivo with a copper exporting CPx-type ATPase CopA. FEMS microbiology letters 76 12644235
2011 The combined actions of the copper-responsive repressor CsoR and copper-metallochaperone CopZ modulate CopA-mediated copper efflux in the intracellular pathogen Listeria monocytogenes. Molecular microbiology 73 21564342
2003 Understanding copper trafficking in bacteria: interaction between the copper transport protein CopZ and the N-terminal domain of the copper ATPase CopA from Bacillus subtilis. Biochemistry 66 12590580
2001 Interaction of the CopZ copper chaperone with the CopA copper ATPase of Enterococcus hirae assessed by surface plasmon resonance. Biochemical and biophysical research communications 57 11594769
2008 High Cu(I) and low proton affinities of the CXXC motif of Bacillus subtilis CopZ. The Biochemical journal 52 18419582
2002 Copper-mediated dimerization of CopZ, a predicted copper chaperone from Bacillus subtilis. The Biochemical journal 51 12238948
2011 Tumor-specific silencing of COPZ2 gene encoding coatomer protein complex subunit ζ 2 renders tumor cells dependent on its paralogous gene COPZ1. Proceedings of the National Academy of Sciences of the United States of America 45 21746916
2003 X-ray absorption and NMR spectroscopic studies of CopZ, a copper chaperone in Bacillus subtilis: the coordination properties of the copper ion. Biochemistry 36 12600214
2024 COPZ1 regulates ferroptosis through NCOA4-mediated ferritinophagy in lung adenocarcinoma. Biochimica et biophysica acta. General subjects 33 39181476
2019 The interplay of the metallosensor CueR with two distinct CopZ chaperones defines copper homeostasis in Pseudomonas aeruginosa. The Journal of biological chemistry 32 30718281
2001 Copper-induced proteolysis of the CopZ copper chaperone of Enterococcus hirae. The Journal of biological chemistry 31 11585824
2008 Structure and dynamics of Cu(I) binding in copper chaperones Atox1 and CopZ: a computer simulation study. The journal of physical chemistry. B 28 18361527
2004 Metal-binding stoichiometry and selectivity of the copper chaperone CopZ from Enterococcus hirae. European journal of biochemistry 28 15009211
2009 A tetranuclear Cu(I) cluster in the metallochaperone protein CopZ. Biochemistry 27 19746989
2016 Streptococcus mutans copper chaperone, CopZ, is critical for biofilm formation and competitiveness. Molecular oral microbiology 24 27753272
2016 Mass spectrometry of B. subtilis CopZ: Cu(i)-binding and interactions with bacillithiol. Metallomics : integrated biometal science 23 27197762
2015 Cytoplasmic CopZ-Like Protein and Periplasmic Rusticyanin and AcoP Proteins as Possible Copper Resistance Determinants in Acidithiobacillus ferrooxidans ATCC 23270. Applied and environmental microbiology 22 26637599
2013 Enhancement of copper content and specific activity of CotA laccase from Bacillus licheniformis by coexpression with CopZ copper chaperone in E. coli. Journal of biotechnology 21 23827415
2009 Mechanistic insights into Cu(I) cluster transfer between the chaperone CopZ and its cognate Cu(I)-transporting P-type ATPase, CopA. The Biochemical journal 21 19751213
2020 COPZ1 depletion in thyroid tumor cells triggers type I IFN response and immunogenic cell death. Cancer letters 19 32061953
2019 The Cu chaperone CopZ is required for Cu homeostasis in Rhodobacter capsulatus and influences cytochrome cbb3 oxidase assembly. Molecular microbiology 19 30582886
2003 Solution structure of apo CopZ from Bacillus subtilis: further analysis of the changes associated with the presence of copper. Biochemistry 19 14621987
2017 Targeting COPZ1 non-oncogene addiction counteracts the viability of thyroid tumor cells. Cancer letters 18 28951131
2012 Importance of electrostatic polarizability in calculating cysteine acidity constants and copper(I) binding energy of Bacillus subtilis CopZ. Journal of computational chemistry 12 22370900
2008 Distinct characteristics of Ag+ and Cd2+ binding to CopZ from Bacillus subtilis. Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry 11 18496720
2004 Metalloregulation in Bacillus subtilis: the copZ chromosomal gene is involved in cadmium resistance. FEMS microbiology letters 11 15212800
2022 BMI1 promotes the proliferation and inhibits autophagy of breast cancer cells by activating COPZ1. Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico 9 35789980
2009 The stress response protein Gls24 is induced by copper and interacts with the CopZ copper chaperone of Enterococcus hirae. FEMS microbiology letters 7 19903200
2025 A new severe congenital neutropenia syndrome associated with autosomal recessive COPZ1 mutations. Blood 3 39642330
2025 COPZ1: an example of non-oncogene addiction in human tumors. Frontiers in pharmacology 0 40978486