Affinage

COPZ1

Coatomer subunit zeta-1 · UniProt P61923

Length
177 aa
Mass
20.2 kDa
Annotated
2026-06-09
35 papers in source corpus 8 papers cited in narrative 8 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

COPZ1 is a subunit of the COPI coatomer that drives retrograde Golgi-to-ER protein transport, and its loss collapses the Golgi, aborts autophagy, and triggers ER stress, the unfolded protein response, and apoptosis in tumor cells (PMID:21746916, PMID:28951131). This dependence is selective: normal cells survive COPZ1 loss because the paralog COPZ2 substitutes, whereas tumor cells silence COPZ2 and are killed by COPZ1 knockdown alone, with COPZ2 re-expression restoring viability (PMID:21746916). Beyond its transport role, COPZ1 governs iron homeostasis by directly binding NCOA4 to restrain ferritinophagy; its depletion stabilizes NCOA4, drives lysosomal degradation of ferritin (FTH1), elevates ferrous iron and lipid peroxidation, and precipitates ferroptosis, an axis reversed by NCOA4 knockdown (PMID:33420375, PMID:39181476). COPZ1 loss also activates type I interferon and viral-mimicry responses that enhance immunogenicity, promoting dendritic cell maturation and cytotoxic T cell killing of tumor cells (PMID:32061953). COPZ1 expression is transcriptionally activated by BMI1, which binds the COPZ1 promoter and counteracts the proliferative and apoptotic consequences of COPZ1 loss (PMID:35789980). Germline autosomal-recessive loss-of-function COPZ1 mutations cause severe congenital neutropenia: truncated COPZ1 shows diminished interaction with the COPI partner COPG1 and impaired retrograde transport, blocking granulocytic differentiation through downregulated JAK/STAT/CEBPE/G-CSFR signaling and induced STING/interferon responses, with rescue by COPZ2 or HIF1α stabilization (PMID:39642330).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2011 High

    Established why tumor cells are selectively vulnerable to COPZ1 loss, defining a paralog-redundancy basis for cancer-specific dependence.

    Evidence siRNA knockdown with Golgi morphology, autophagy, apoptosis assays and COPZ2 rescue across multiple cell lines

    PMID:21746916

    Open questions at the time
    • Did not resolve which COPI cargoes mediate the lethal phenotype
    • Mechanism linking Golgi collapse to apoptosis not dissected
  2. 2017 Medium

    Extended the COPZ1-loss death program to a defined ER-stress/UPR cascade and validated the dependency in vivo.

    Evidence siRNA knockdown, ER stress/UPR western blots, autophagy and apoptosis assays, mouse xenografts in thyroid tumor cells

    PMID:28951131

    Open questions at the time
    • Single tumor lineage and lab
    • Causal ordering of abortive autophagy vs ER stress unresolved
  3. 2020 Medium

    Showed that COPZ1 loss is not merely cytotoxic but immunogenic, linking transport disruption to interferon and viral-mimicry responses.

    Evidence siRNA knockdown with secretome transcriptomics/proteomics, dendritic cell maturation and T cell cytotoxicity assays

    PMID:32061953

    Open questions at the time
    • Molecular trigger of viral mimicry not identified
    • Single lab and lineage
  4. 2021 High

    Identified a new COPZ1 function in iron metabolism by linking its loss to NCOA4 stabilization, ferritin degradation, and ferroptosis.

    Evidence siRNA/shRNA knockdown, NCOA4/FTH1 western blots, intracellular iron measurement, cell death assays and xenografts in glioblastoma

    PMID:33420375

    Open questions at the time
    • Did not establish whether COPZ1 regulates NCOA4 directly or via transport
    • No physical interaction shown at this stage
  5. 2022 Medium

    Placed COPZ1 downstream of an oncogenic transcriptional regulator, explaining how COPZ1 levels are set in tumors.

    Evidence Luciferase reporter and ChIP for BMI1 promoter binding, knockdown and BMI1 overexpression rescue in breast cancer cells

    PMID:35789980

    Open questions at the time
    • Whether BMI1 regulation operates in non-breast lineages unknown
    • Other transcriptional inputs not characterized
  6. 2024 Medium

    Provided the physical and epistatic basis for the iron axis by demonstrating direct COPZ1-NCOA4 binding and NCOA4-dependent reversal of the ferroptotic phenotype.

    Evidence Co-IP for direct binding, double knockdown rescue, ROS/Fe2+/lipid peroxidation and mitochondrial imaging in lung adenocarcinoma

    PMID:39181476

    Open questions at the time
    • Binding interface and stoichiometry undefined
    • Co-IP without reciprocal/structural validation
  7. 2025 High

    Connected COPZ1 to a human Mendelian disease, showing that loss-of-function mutations impair COPI assembly and retrograde transport to block granulopoiesis.

    Evidence Patient mutations, COPG1 interaction and retrograde transport assays, CD34+ differentiation, zebrafish myelopoiesis, signaling dissection, COPZ2/IOX2 rescue

    PMID:39642330

    Open questions at the time
    • How transport defect mechanistically silences JAK/STAT/CEBPE/G-CSFR not fully resolved
    • Genotype-phenotype range across mutations not established
  8. 2025 Low

    Implicated COPZ1-containing COPI in HDL receptor trafficking and lipid handling in hepatocytes.

    Evidence Genome-wide RNAi screen with siRNA validation, surface receptor flow cytometry, apoA-I secretion and cholesterol efflux assays (preprint)

    PMID:bio_10.1101_2025.08.21.25332476

    Open questions at the time
    • COPZ1 is one of six COPI subunits with shared phenotype; COPZ1-specific role not isolated
    • Preprint, not peer reviewed

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown how a single core COPI subunit selectively governs distinct outputs (ferritinophagy, interferon responses, granulocyte signaling) beyond its general retrograde transport role.
  • No structural model of COPZ1 within the coatomer
  • Mechanism connecting transport disruption to each downstream pathway undefined
  • Specific COPI cargoes responsible for each phenotype not identified

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 2 GO:0005783 endoplasmic reticulum 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-1430728 Metabolism 2 R-HSA-168256 Immune System 2 R-HSA-9609507 Protein localization 2 R-HSA-9612973 Autophagy 2
Partners
BMI1COPG1COPZ2NCOA4
Complex memberships
COPI coatomer

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 COPZ1 knockdown in tumor cells causes Golgi apparatus collapse, blocks autophagy, and induces apoptosis in both proliferating and non-dividing tumor cells, while normal cells required simultaneous knockdown of both COPZ1 and COPZ2 for growth inhibition. Re-expression of COPZ2 protected tumor cells from COPZ1 knockdown-induced death, demonstrating that tumor cell dependence on COPZ1 results from COPZ2 silencing. siRNA knockdown, cell viability assays, immunofluorescence of Golgi morphology, autophagy assays, apoptosis assays, COPZ2 rescue experiment 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 stress, unfolded protein response (UPR), and apoptosis. COPZ1 knockdown also reduced tumor growth in mouse xenograft models. siRNA knockdown, western blot for ER stress/UPR markers, autophagy assays, apoptosis assays, in vivo xenograft tumor growth Cancer letters Medium 28951131
2021 COPZ1 knockdown in glioblastoma cells increases nuclear receptor coactivator 4 (NCOA4) levels, leading to ferritin degradation, elevated intracellular ferrous iron, and ultimately ferroptosis. COPZ1 thus acts as a critical mediator of iron metabolism via the COPZ1/NCOA4/FTH1 axis. siRNA/shRNA knockdown, western blot for NCOA4 and FTH1, intracellular iron measurement, cell death assays, in vivo xenograft model Oncogene High 33420375
2020 COPZ1 depletion in thyroid tumor cells activates type I interferon pathway and viral mimicry responses, enriches the secretome for inflammatory molecules and damage-associated molecular patterns (DAMPs), promotes dendritic cell maturation, and stimulates cytotoxic T cell activity against tumor cells. siRNA knockdown, transcriptomic/proteomic secretome analysis, dendritic cell co-culture maturation assays, T cell proliferation and cytotoxicity assays Cancer letters Medium 32061953
2024 COPZ1 directly binds NCOA4; COPZ1 knockdown restricts FTH1 expression, promotes NCOA4 and LC3 expression, and induces translocation of ferritin to lysosomes for degradation (ferritinophagy). NCOA4 knockdown reverses the iron metabolism, lipid peroxidation, and mitochondrial structural changes induced by COPZ1 knockdown in lung adenocarcinoma cells. Co-immunoprecipitation (direct binding of COPZ1 to NCOA4), siRNA knockdown, western blot, ROS/Fe2+/lipid peroxidation measurements, mitochondrial morphology imaging, lysosomal fractionation, xenograft model Biochimica et biophysica acta. General subjects Medium 39181476
2022 BMI1 transcriptionally activates COPZ1 by binding to the COPZ1 promoter, as demonstrated by luciferase reporter assay and ChIP. BMI1 overexpression reverses the effects of COPZ1 knockdown on proliferation, apoptosis, and autophagy in breast cancer cells, placing COPZ1 downstream of BMI1 in this pathway. Luciferase reporter assay, ChIP, siRNA knockdown, BMI1 overexpression rescue, western blot for proliferation/apoptosis/autophagy markers Clinical & translational oncology Medium 35789980
2025 Autosomal recessive loss-of-function mutations in COPZ1 (truncating and missense) cause severe congenital neutropenia with impaired granulocytic differentiation. The truncated COPZ1 protein shows diminished interaction with COPI complex partner COPG1, and human fibroblasts with truncated COPZ1 display a block in retrograde protein transport from the Golgi to the ER. COPZ1 loss downregulates JAK/STAT/CEBPE/G-CSFR signaling and hypoxia-responsive pathways while inducing STING and interferon-stimulated genes, and increasing ROS in hematopoietic cells. COPZ2 transduction or HIF1α stabilizer IOX2 restored defective granulopoiesis. Patient-derived mutations, protein interaction prediction and functional validation, retrograde transport assay in human fibroblasts, CD34+ cell differentiation assay, zebrafish myelopoiesis assay, signaling pathway analysis, pharmacological rescue with IOX2 and COPZ2 lentiviral transduction Blood High 39642330
2025 Knockdown of COPZ1 (along with five other COPI subunits) in Huh-7 hepatocarcinoma cells decreases HDL holoparticle uptake, reduces SR-BI cell surface abundance (implicating impaired SR-BI glycosylation), reduces APOA1 expression and apoA-I secretion, but increases ABCA1 cell surface abundance and cholesterol efflux. Genome-wide RNAi screen, targeted siRNA knockdown validation, flow cytometry for surface receptors, apoA-I secretion assay, cholesterol efflux assay bioRxivpreprint Low bio_10.1101_2025.08.21.25332476

Source papers

Stage 0 corpus · 35 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2021 Loss of COPZ1 induces NCOA4 mediated autophagy and ferroptosis in glioblastoma cell lines. Oncogene 150 33420375
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 77 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 74 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
2024 COPZ1 regulates ferroptosis through NCOA4-mediated ferritinophagy in lung adenocarcinoma. Biochimica et biophysica acta. General subjects 38 39181476
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
2019 The interplay of the metallosensor CueR with two distinct CopZ chaperones defines copper homeostasis in Pseudomonas aeruginosa. The Journal of biological chemistry 35 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 25 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 23 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 5 39642330
2025 COPZ1: an example of non-oncogene addiction in human tumors. Frontiers in pharmacology 0 40978486

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