Affinage

COX5B

Cytochrome c oxidase subunit 5B, mitochondrial · UniProt P10606

Round 2 corrected
Length
129 aa
Mass
13.7 kDa
Annotated
2026-04-28
47 papers in source corpus 12 papers cited in narrative 12 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

COX5B is a nuclear-encoded peripheral subunit of mitochondrial cytochrome c oxidase (Complex IV), structurally resolved within the intact 14-subunit human complex at 3.3 Å by cryo-EM (PMID:30030519). COX5B is required for electron transport chain integrity: its loss causes mitochondrial membrane depolarization, elevated ROS, decreased ATP production, cellular senescence, and suppressed proliferation across breast cancer, glioma, NSCLC, colorectal cancer, and testicular cell models (PMID:26506233, PMID:39586785, PMID:41213905). Beyond bioenergetics, COX5B physically interacts with MAVS at the mitochondrial membrane and negatively regulates antiviral innate immune signaling by suppressing ROS production and coordinating with ATG5-dependent autophagy to limit MAVS aggregation (PMID:23308066). COX5B mRNA stability and translation are post-transcriptionally promoted by TRDMT1-mediated m5C modification at C-153, read by YBX1, and its expression is regulated upstream by MZT2B and NDUFS4 to sustain OXPHOS-dependent tumor cell growth (PMID:40253045, PMID:41213905, PMID:41617910).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 1988 Medium

    Identification of a trans-acting repressor of COX5b under aerobic conditions in yeast established that COX5B expression is subject to oxygen-dependent transcriptional regulation, raising the question of what cis-elements mediate this control.

    Evidence Suppressor mutation screen and complementation grouping in S. cerevisiae

    PMID:2852136

    Open questions at the time
    • REO1 gene product not molecularly characterized
    • mechanism of oxygen sensing upstream of REO1 unknown
    • relevance to mammalian COX5B regulation not tested
  2. 1990 Medium

    Dissection of the yeast COX5b promoter revealed discrete cis-elements (two UAS elements, a URS for aerobic repression, and a TATA region), explaining how carbon source and oxygen signals converge on COX5b transcription.

    Evidence Deletion analysis of upstream regulatory region with heterologous reporter assays in S. cerevisiae

    PMID:2169024

    Open questions at the time
    • Trans-acting factors binding these elements not identified
    • conservation of regulatory architecture in mammals untested
  3. 2012 High

    Discovery that COX5B physically interacts with MAVS and negatively regulates antiviral innate immune signaling revealed an unexpected non-bioenergetic function: COX5B restrains MAVS aggregation by suppressing ROS and cooperating with ATG5/autophagy, establishing a feedback loop between mitochondrial electron transport and innate immunity.

    Evidence Reciprocal co-immunoprecipitation, ROS measurement, knockdown/overexpression of COX5B with antiviral signaling readouts, autophagy pathway interaction assays in human cells

    PMID:23308066

    Open questions at the time
    • Structural basis of COX5B–MAVS interaction unknown
    • Whether COX5B's immune-regulatory role is independent of its Complex IV function not resolved
  4. 2015 Medium

    Functional loss-of-function studies in breast cancer cells demonstrated that COX5B is required to maintain mitochondrial electron transport, ROS homeostasis, ATP production, and proliferation, with knockdown inducing senescence and metabolic reprogramming — establishing COX5B as a non-redundant Complex IV subunit for cell fitness.

    Evidence SILAC proteomics, shRNA knockdown, ROS/ATP/MMP measurements, proliferation and senescence assays, metabolic flux analysis in breast cancer cells

    PMID:26506233

    Open questions at the time
    • Whether other Complex IV subunits can compensate unknown
    • Metabolic reprogramming mechanism not fully delineated
  5. 2018 High

    Cryo-EM resolution of the intact human Complex IV at 3.3 Å provided the first high-resolution structural context for COX5B within the 14-subunit enzyme, confirming subunit positions and the architecture of the respiratory supercomplex.

    Evidence Cryo-EM structure determination from human supercomplex I₁III₂IV₁

    PMID:30030519

    Open questions at the time
    • COX5B-specific contact surfaces and conformational dynamics not analyzed in detail
    • No structure of COX5B assembly intermediates
  6. 2020 Medium

    Identification of a COX5B–AMPK–UHMK1–ERK signaling axis in hepatoma cells revealed how COX5B-dependent bioenergetic output is transduced into oncogenic signaling, explaining the pro-tumorigenic role of COX5B beyond simple OXPHOS maintenance.

    Evidence Loss/gain-of-function, cDNA microarray, phosphoproteomics, xenograft models in hepatoma cells

    PMID:32580279

    Open questions at the time
    • AMPK activation mechanism by COX5B-derived ATP not mechanistically detailed
    • Generalizability of UHMK1 axis across tumor types untested
  7. 2021 Medium

    In colorectal cancer, COX5B was shown to sustain proliferation and drug resistance through upregulation of Claudin-2, extending the downstream effector repertoire of COX5B-mediated bioenergetic signaling to tight junction proteins.

    Evidence COX5B silencing, RNA-seq, functional rescue experiments in colorectal cancer cells

    PMID:35052740

    Open questions at the time
    • Mechanism linking bioenergetic changes to CLDN2 transcription not identified
    • Single cancer model
  8. 2024 Medium

    Demonstration that COX5B knockdown aggravates senescence and mitochondrial dysfunction in testicular cells extended its essential bioenergetic role to a non-cancer, hormone-responsive tissue context.

    Evidence Cryptorchid rat model and COX5B knockdown in TM3 Leydig cells with ROS/ATP/MMP and senescence readouts

    PMID:39586785

    Open questions at the time
    • Mechanism of COX5B downregulation in cryptorchidism not elucidated
    • In vivo testicular phenotype of COX5B loss not fully characterized
  9. 2025 Medium

    Elucidation of the TRDMT1-m5C-YBX1 post-transcriptional axis controlling COX5B mRNA stability and translation revealed a previously unknown epitranscriptomic layer of COX5B regulation, showing that m5C modification at C-153 and recognition by YBX1 (Lys-92) directly controls COX5B protein levels.

    Evidence m5C methylation assays, YBX1 binding assays, exosome delivery, site-directed mutagenesis of YBX1 Lys-92, ROS/mitochondrial function readouts in granulosa cells

    PMID:40253045

    Open questions at the time
    • Whether m5C regulation of COX5B is tissue-general or specific to granulosa cells unknown
    • Other epitranscriptomic modifications on COX5B mRNA not surveyed
  10. 2025 Medium

    Genetic rescue experiments placed COX5B as a critical downstream effector of both MZT2B (in NSCLC) and NDUFS4 (in glioma), demonstrating that transcriptional control of COX5B by upstream regulators is a convergent mechanism sustaining OXPHOS and tumor growth across cancer types.

    Evidence shRNA/CRISPR knockout of MZT2B and NDUFS4; COX5B overexpression rescue; OCR measurement; xenograft and intracranial models

    PMID:41213905 PMID:41617910

    Open questions at the time
    • Transcription factors mediating MZT2B→COX5B and NDUFS4→COX5B regulation not identified
    • Whether COX5B is the sole critical effector or one of several downstream targets unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis of COX5B's interaction with MAVS, the transcription factors linking upstream regulators (MZT2B, NDUFS4) to COX5B expression, and whether COX5B has moonlighting functions independent of Complex IV catalytic activity remain unresolved.
  • No crystal or cryo-EM structure of COX5B–MAVS interface
  • Transcriptional regulatory mechanisms connecting MZT2B/NDUFS4 to COX5B promoter undefined
  • No reconstitution experiments separating COX5B's Complex IV role from potential non-canonical functions

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 1 GO:0016491 oxidoreductase activity 1 GO:0098772 molecular function regulator activity 1
Localization
GO:0005739 mitochondrion 4
Pathway
R-HSA-1430728 Metabolism 4 R-HSA-8953897 Cellular responses to stimuli 2 R-HSA-168256 Immune System 1
Partners
ATG5MAVSMZT2BNDUFS4TRDMT1YBX1
Complex memberships
Cytochrome c oxidase (Complex IV)Respiratory supercomplex I1III2IV1

Evidence

Reading pass · 12 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1988 In S. cerevisiae, REO1 (Regulator of Expression of Oxidase) was identified as a gene that negatively regulates COX5b expression specifically under aerobic conditions. reo1 mutations are recessive, unlinked to COX5b, and increase COX5b expression aerobically but not anaerobically, placing REO1 upstream of COX5b as a repressor in the oxygen-dependent regulatory pathway. Genetic epistasis analysis; suppressor mutation screen; complementation grouping Genetics Medium 2852136
1990 In S. cerevisiae, the COX5b promoter contains at least four distinct regulatory elements: two upstream activating sequences (UAS1(5b) and UAS2(5b)), one upstream repression sequence (URS5b), and a TATA-like region. UAS1(5b) mediates carbon source control and contains two synergistically acting domains; URS5b mediates aerobic repression of COX5b and contains sequences conserved in other oxygen-regulated yeast genes. Deletion analysis of upstream regulatory region; heterologous reporter gene assays Molecular and cellular biology Medium 2169024
2012 Human COX5B physically interacts with MAVS at the mitochondrial membrane and negatively regulates MAVS-mediated antiviral signaling. Mechanistically, MAVS activation induces ROS production and upregulates COX5B expression; COX5B in turn suppresses MAVS signaling by repressing ROS production. Additionally, COX5B coordinates with the autophagy pathway (via ATG5) to control MAVS aggregation, thereby limiting antiviral signal amplitude. Co-immunoprecipitation; ROS measurement; knockdown and overexpression with antiviral signaling readouts; autophagy pathway interaction assays PLoS pathogens High 23308066
2015 Loss of COX5B in breast cancer cell lines induces mitochondrial dysfunction characterized by increased ROS production, depolarization of mitochondrial membrane potential, and decreased ATP levels. COX5B knockdown suppresses cell proliferation, induces cellular senescence, and causes metabolic reprogramming (increased glucose uptake, decreased lactate secretion), positioning COX5B as required for mitochondrial electron transport function and metabolic homeostasis. SILAC proteomics; shRNA knockdown; ROS/ATP/MMP measurements; proliferation and senescence assays; metabolic flux analysis Oncotarget Medium 26506233
2018 Cryo-EM structure of the intact 14-subunit human cytochrome c oxidase (Complex IV) at 3.3 Å resolution revealed the structural positions of all subunits within the complex, including COX5B, and confirmed that NDUFA4 is a bona fide subunit of Complex IV rather than Complex I, occupying the position at the dimeric interface and precluding CcO dimerization. Cryo-EM structure determination at 3.3 Å from human supercomplex I1III2IV1 Cell research High 30030519
2020 In hepatoma cells, COX5B promotes tumor growth and migration through a bioenergetic alteration-dependent mechanism: COX5B expression sustains OXPHOS/ATP levels, which activates AMPK signaling, which in turn upregulates the oncogenic kinase UHMK1. Phosphoproteomic analysis identified ERK- and stathmin-mediated pathways as downstream of UHMK1, establishing a COX5B–AMPK–UHMK1–ERK signaling axis. Loss- and gain-of-function experiments; cDNA microarray; phosphoproteomic analysis; xenograft models Cancers Medium 32580279
2021 In colorectal cancer cells, COX5B promotes cell growth and reduces susceptibility to anticancer drugs through bioenergetic alterations that upregulate the tight junction protein Claudin-2 (CLDN2). RNA sequencing followed by functional compensation experiments demonstrated CLDN2 acts downstream of COX5B-mediated bioenergetic changes to control proliferation and drug sensitivity. COX5B silencing; RNA sequencing; RT-qPCR; functional compensation/rescue experiments Biomedicines Medium 35052740
2024 In cryptorchid rat testis and TM3 cells, COX5B knockdown aggravates cellular senescence, reduces proliferation, and induces mitochondrial dysfunction (increased ROS, decreased ATP, reduced mitochondrial membrane potential), demonstrating that COX5B expression is required for normal mitochondrial function in testicular cells. Cryptorchid rat model; COX5B knockdown in TM3 cells; ROS/ATP/MMP measurements; senescence and proliferation assays Journal of cellular and molecular medicine Medium 39586785
2025 TRDMT1-mediated 5-methylcytosine (m5C) RNA modification of COX5B mRNA promotes its translation. The m5C reader YBX1, delivered via human umbilical cord MSC-derived exosomes (H-Ex), directly binds the m5C-modified COX5B mRNA at residue C-153 via LYS-92, stabilizing COX5B mRNA and increasing COX5B protein levels to reduce ROS and improve mitochondrial function in oxidatively stressed granulosa cells. m5C methylation assays; YBX1 binding assays; exosome delivery experiments; site-directed mutagenesis (YBX1 LYS-92); ROS/mitochondrial function readouts International journal of biological macromolecules Medium 40253045
2025 MZT2B (mitotic spindle organizing protein 2B) regulates COX5B expression in NSCLC cells; COX5B acts as a critical downstream effector of MZT2B. Restoring COX5B expression in MZT2B-depleted cells rescued mitochondrial respiration, ATP production, and malignant phenotypes, demonstrating that the MZT2B→COX5B axis is required for mitochondrial function and NSCLC tumor growth. shRNA and CRISPR/Cas9 knockout; COX5B rescue overexpression; oxygen consumption rate measurement; xenograft models Cell death & disease Medium 41213905
2025 NDUFS4 (Complex I subunit) regulates COX5B expression in glioma cells; COX5B is an important downstream effector of NDUFS4. Silencing COX5B in primary glioma cells replicated the anti-proliferative and pro-apoptotic effects of NDUFS4 depletion, and restoring COX5B expression in NDUFS4-silenced cells rescued these effects, establishing a functional NDUFS4→COX5B regulatory axis in mitochondrial function and glioma progression. shRNA silencing; CRISPR/Cas9 knockout; COX5B rescue experiments; oxygen consumption rate; in vivo intracranial xenograft NPJ precision oncology Medium 41617910
2025 Berberine targets COX5B in lung adenocarcinoma cells, diminishing COX5B protein expression and consequently disrupting redox homeostasis and inhibiting cell proliferation and tumor growth, identifying COX5B as a pharmacologically tractable node in OXPHOS-dependent tumor growth. COX5B knockdown; berberine treatment; flow cytometry; EdU proliferation assays; electron microscopy; Western blot Oncology research Low 41502520

Source papers

Stage 0 corpus · 47 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 1718 22658674
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
2006 A germline-specific class of small RNAs binds mammalian Piwi proteins. Nature 1362 16751776
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2011 A proteome-wide, quantitative survey of in vivo ubiquitylation sites reveals widespread regulatory roles. Molecular & cellular proteomics : MCP 749 21890473
2007 Large-scale mapping of human protein-protein interactions by mass spectrometry. Molecular systems biology 733 17353931
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
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2015 Panorama of ancient metazoan macromolecular complexes. Nature 407 26344197
2021 A proximity-dependent biotinylation map of a human cell. Nature 339 34079125
2007 Huntingtin interacting proteins are genetic modifiers of neurodegeneration. PLoS genetics 325 17500595
2016 Identification of Zika Virus and Dengue Virus Dependency Factors using Functional Genomics. Cell reports 306 27342126
2019 Mitochondrial ClpP-Mediated Proteolysis Induces Selective Cancer Cell Lethality. Cancer cell 298 31056398
2015 Inhibition of the Mitochondrial Protease ClpP as a Therapeutic Strategy for Human Acute Myeloid Leukemia. Cancer cell 293 26058080
2020 Virus-Host Interactome and Proteomic Survey Reveal Potential Virulence Factors Influencing SARS-CoV-2 Pathogenesis. Med (New York, N.Y.) 291 32838362
2020 Phosphorylated tau interactome in the human Alzheimer's disease brain. Brain : a journal of neurology 290 32812023
2010 Mass spectrometric analysis of lysine ubiquitylation reveals promiscuity at site level. Molecular & cellular proteomics : MCP 262 21139048
2022 CST1 inhibits ferroptosis and promotes gastric cancer metastasis by regulating GPX4 protein stability via OTUB1. Oncogene 259 36369321
2012 Systems-wide analysis of ubiquitylation dynamics reveals a key role for PAF15 ubiquitylation in DNA-damage bypass. Nature cell biology 243 23000965
2021 Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context. Cell metabolism 239 34800366
2018 An AP-MS- and BioID-compatible MAC-tag enables comprehensive mapping of protein interactions and subcellular localizations. Nature communications 201 29568061
2011 Next-generation sequencing to generate interactome datasets. Nature methods 200 21516116
2018 Structure of the intact 14-subunit human cytochrome c oxidase. Cell research 175 30030519
2014 Global mapping of herpesvirus-host protein complexes reveals a transcription strategy for late genes. Molecular cell 173 25544563
2005 Large-scale analysis of the human ubiquitin-related proteome. Proteomics 154 16196087
2012 COX5B regulates MAVS-mediated antiviral signaling through interaction with ATG5 and repressing ROS production. PLoS pathogens 109 23308066
2015 Loss of COX5B inhibits proliferation and promotes senescence via mitochondrial dysfunction in breast cancer. Oncotarget 36 26506233
1990 Upstream activation and repression elements control transcription of the yeast COX5b gene. Molecular and cellular biology 29 2169024
1988 Identification of REO1, a gene involved in negative regulation of COX5b and ANB1 in aerobically grown Saccharomyces cerevisiae. Genetics 28 2852136
2020 COX5B-Mediated Bioenergetic Alteration Regulates Tumor Growth and Migration by Modulating AMPK-UHMK1-ERK Cascade in Hepatoma. Cancers 23 32580279
2004 The promoter of the Arabidopsis nuclear gene COX5b-1, encoding subunit 5b of the mitochondrial cytochrome c oxidase, directs tissue-specific expression by a combination of positive and negative regulatory elements. Journal of experimental botany 23 15286148
2017 Decreased Tissue COX5B Expression and Mitochondrial Dysfunction during Sepsis-Induced Kidney Injury in Rats. Oxidative medicine and cellular longevity 20 28246552
2017 Identification of COX5B as a novel biomarker in high-grade glioma patients. OncoTargets and therapy 18 29180880
2009 Characterization of promoter elements required for expression and induction by sucrose of the Arabidopsis COX5b-1 nuclear gene, encoding the zinc-binding subunit of cytochrome c oxidase. Plant molecular biology 18 19125337
2009 Identification of regulatory elements involved in expression and induction by sucrose and UV-B light of the Arabidopsis thaliana COX5b-2 gene, encoding an isoform of cytochrome c oxidase subunit 5b. Physiologia plantarum 14 19781003
2021 COX5B-Mediated Bioenergetic Alterations Modulate Cell Growth and Anticancer Drug Susceptibility by Orchestrating Claudin-2 Expression in Colorectal Cancers. Biomedicines 13 35052740
2025 HuMSCs-derived exosomal YBX1 participates in oxidative damage repair in granulosa cells by stabilizing COX5B mRNA in an m5C-dependent manner. International journal of biological macromolecules 6 40253045
2024 Abnormal Expression of COX5B Gene and Disorder of Mitochondrial Function in Cryptorchid Rats. Journal of cellular and molecular medicine 4 39586785
2026 Mitochondrial complex I subunit NDUFS4 overexpression drives glioma progression by regulating mitochondrial function and COX5B. NPJ precision oncology 0 41617910
2025 MZT2B promotes malignant phenotypes in NSCLC cells by enhancing mitochondrial function and COX5B expression. Cell death & disease 0 41213905
2025 Mitochondrial protein COX5B orchestrates antiviral autophagy and apoptosis to restrict SRBSDV propagation in Sogatella furcifera. Autophagy 0 41358576
2025 Integrative Multi-Omics Analysis and Experiments Validation Identify COX5B as a Novel Therapeutic Target for Lung Adenocarcinoma. Oncology research 0 41502520