CDO1

CDO1 is a non-heme iron(II)-dependent dioxygenase that catalyzes the oxidation of cysteine to cysteine sulfinic acid, serving as the essential and rate-limiting entry point for taurine biosynthesis (PMID:28849476). Its enzymatic activity is post-translationally regulated by AKT1-mediated phosphorylation at T89, which disrupts iron incorporation (PMID:40269955), and by glutathionylation at C164 under oxidative stress, which impairs substrate binding (PMID:40347691); its protein abundance is controlled by TRIM47-mediated K48-linked ubiquitination in hepatocellular carcinoma (PMID:38614226) and by the LRRC58-CUL2 cullin-RING E3 ligase that conditionally degrades CDO1 at Lys8 under cysteine deprivation to prevent ferroptosis [PMID:bio_10.1101_2025.11.14.688510, PMID:bio_10.1101_2025.09.23.678073]. Beyond cysteine catabolism, CDO1 functions as a transcriptional co-activator by interacting with PPARγ and recruiting the mediator subunit Med24 to lipolytic gene promoters in adipose tissue (PMID:36253617), and scaffolds Camkk2–AMPK to activate fatty acid oxidation and mitochondrial biogenesis in hepatocytes downstream of exercise-induced cAMP/PKA/CREB signaling (PMID:38110408). CDO1 promoter hypermethylation by DNMT1 (recruited by lncRNA FAM83H-AS1) and DNMT3A silences CDO1 expression across multiple cancers, conferring ferroptosis resistance and promoting tumor progression (PMID:39159808, PMID:38308276, PMID:37740473).

1. 2014 Medium

   Whether CDO1 silencing in cancer is epigenetically driven was addressed by demonstrating that CDO1 promoter DNA methylation inversely correlates with CDO1 expression across diverse cancer cell lines, establishing promoter methylation as the primary silencing mechanism.

   Evidence Quantitative methylation-specific PCR paired with RT-PCR across 74 cancer cell lines

   PMID:24948044

   Open questions at the time

   • Correlation-based; no functional demethylation rescue performed in this study
   • Upstream factors recruiting DNMTs to CDO1 promoter not identified
2. 2017 High

   Whether CDO1 is the obligate enzyme for taurine biosynthesis was resolved by showing that Cdo1-null mice lack hypotaurine and taurine in all tissues, and dietary taurine supplementation rescues downstream hepatic gene expression changes.

   Evidence Cdo1-null mouse model with dietary taurine rescue and hepatic gene expression profiling

   PMID:28849476

   Open questions at the time

   • Whether CDO1 has cysteine-independent enzymatic substrates in vivo remains untested
   • Contribution of cysteamine dioxygenase activity versus cysteine dioxygenase activity not dissected
3. 2022 High

   Whether CDO1 has functions beyond cysteine catabolism was answered by discovering that CDO1 interacts with PPARγ and recruits the mediator subunit Med24 to ATGL/HSL promoters, transactivating lipolysis in adipose tissue independently of its enzymatic activity.

   Evidence Co-IP of CDO1–PPARγ, ChIP for Med24 at promoters, adipose-specific KO and overexpression mouse models with lipolysis and obesity phenotypes

   PMID:36253617

   Open questions at the time

   • Whether the co-activator function requires the CDO1 iron-binding site or is structurally separable from enzymatic activity
   • Direct DNA-binding contribution of CDO1 versus purely scaffolding role not resolved
4. 2023 High

   CDO1's non-enzymatic scaffolding role was extended to hepatic AMPK signaling, where CDO1 physically tethers Camkk2 to AMPK to activate fatty acid oxidation and mitochondrial biogenesis, with hepatic expression induced by the cAMP/PKA/CREB axis during exercise.

   Evidence Co-IP of CDO1–Camkk2 and CDO1–AMPK, hepatocyte-specific KO and overexpression mice with NAFLD readouts and upstream pathway dissection

   PMID:38110408

   Open questions at the time

   • Structural basis for CDO1 scaffolding Camkk2–AMPK unknown
   • Whether enzymatic and scaffolding functions of CDO1 are simultaneously active in the same cell
5. 2023 Medium

   Functional causation of epigenetic silencing was demonstrated: targeted demethylation of the CDO1 promoter by dCas9-Tet1CD restores CDO1 expression and induces ferroptosis, apoptosis, and growth suppression in breast cancer cells, and the HBP1–UHRF1 axis epigenetically regulates CDO1 to control ferroptosis sensitivity.

   Evidence CRISPR/dCas9-Tet1CD epigenetic editing with functional phenotypic assays; HBP1 overexpression–UHRF1 epistasis in HCC/cervical cancer cells

   PMID:37406020 PMID:37740473

   Open questions at the time

   • Whether CDO1's ferroptosis-promoting function operates through cysteine depletion, taurine production, or an independent mechanism is not fully resolved
   • Single-lab studies for each
6. 2024 High

   How CDO1 protein abundance is regulated by ubiquitination was clarified: TRIM47 ubiquitinates CDO1 via K48-linkage through its B30.2 domain in HCC, suppressing CDO1-mediated ferroptosis and promoting tumor progression; meanwhile, DNMT1 is recruited to the CDO1 promoter by lncRNA FAM83H-AS1 in endometrial cancer and DNMT3A silences CDO1 in HCC.

   Evidence Co-IP with domain mapping, K48 ubiquitination assays, ferroptosis rescue; RIP and ChIP for lncRNA–DNMT1–CDO1 promoter; MSP and dual-luciferase for DNMT3A

   PMID:38308276 PMID:38614226 PMID:39159808

   Open questions at the time

   • Relative contributions of transcriptional silencing versus post-translational degradation to CDO1 loss in individual tumor contexts not quantified
   • Whether TRIM47 and LRRC58 compete for CDO1 binding
7. 2025 High

   Post-translational regulation of CDO1 enzymatic activity was mechanistically resolved: AKT1 phosphorylates CDO1 at T89 to disrupt iron incorporation and repress activity (promoting OSCC growth), while oxidative stress-induced glutathionylation at C164 impairs substrate binding and is required for redox homeostasis under ionizing radiation.

   Evidence Kinase assay with AKT1, T89 mutagenesis, iron incorporation and enzymatic activity assays; C164 mutagenesis, glutathionylation biochemistry, radiation survival assays

   PMID:40269955 PMID:40347691

   Open questions at the time

   • Whether T89 phosphorylation and C164 glutathionylation occur simultaneously or are mutually exclusive
   • Structural consequences of these PTMs not visualized at atomic resolution
8. 2025 High

   A cysteine-sensing degradation circuit for CDO1 was defined: LRRC58 assembles a CUL2/CUL5-based E3 ligase that ubiquitylates CDO1 at Lys8 for proteasomal degradation under cysteine deprivation; LRRC58 itself is auto-ubiquitinated and degraded when cysteine is abundant, creating a substrate-sensing toggle that prevents ferroptosis.

   Evidence Cryo-EM structure of CDO1–LRRC58–CRL complex, biochemical reconstitution, saturation mutagenesis, ferroptosis assays (two independent preprints)

   PMID:bio_10.1101_2025.09.23.678073 PMID:bio_10.1101_2025.11.14.688510

   Open questions at the time

   • Preprint status; peer review pending
   • How LRRC58 senses cysteine concentration at the molecular level (cysteine-binding site on LRRC58 not mapped)
   • Disease-associated CDO1 mutations refractory to LRRC58: clinical characterization incomplete

• How CDO1's enzymatic and non-enzymatic (scaffolding/co-activator) functions are coordinated in the same cell, whether they are mutually exclusive or operate in distinct subcellular pools, and the structural basis for the co-activator interaction with PPARγ remain unresolved.
• No structure of CDO1–PPARγ–Med24 complex
• Whether enzymatic-dead CDO1 mutants retain full scaffolding/co-activator function not systematically tested
• In vivo tissue-specific balance of cysteine catabolism versus signaling functions not quantified