COMMD10

COMMD10 is a member of the COMMD/CCC complex that acts as a regulator of protein trafficking, metal homeostasis, and inflammatory signaling across epithelial and myeloid cell types (PMID:30959277, PMID:29997525). It functions as a negative regulator of NF-κB signaling by binding the p65 subunit and reducing its nuclear translocation; this activity is itself controlled by FMNL2, which physically interacts with COMMD10 and targets it for ubiquitin-mediated proteasomal degradation (PMID:28817833). COMMD10 promotes the ubiquitin-dependent proteasomal degradation of HIF1α and constrains copper accumulation, and loss of this activity (for example following ionizing radiation) stabilizes HIF1α and drives transcription of ceruloplasmin and SLC7A11 to suppress ferroptosis (PMID:35101526). In macrophages, COMMD10 supports TFEB-driven lysosomal biogenesis and phagolysosomal maturation required for bacterial clearance, sustains tissue-resident macrophage survival, and restrains canonical and non-canonical inflammasome (caspase-1/11) activation in Ly6Chi monocytes (PMID:30959277, PMID:30487795, PMID:34788631). In epithelial cells COMMD10 binds the epithelial Na+ channel (ENaC) and positively regulates its current by antagonizing Nedd4-2 while also influencing endocytic trafficking (PMID:29997525). COMMD10 is essential for neural plate and neural crest development, with knockout embryos arresting by E8.5 and showing loss of neural crest transcription factors including Sox10 (PMID:36976102).

1. 2017 High

   Established COMMD10 as a node controlling its own stability and NF-κB output, answering how an upstream factor (FMNL2) tunes inflammatory and metastatic signaling.

   Evidence Reciprocal Co-IP, GST pull-down, in vitro ubiquitination, and dual-luciferase reporter assays in colorectal cancer cells

   PMID:28817833

   Open questions at the time

   • Domain/residues mediating COMMD10–p65 binding not mapped
   • Whether FMNL2 is the ubiquitin ligase or a recruiter not resolved
2. 2018 Medium

   Defined a cell-type-specific role for COMMD10 as a brake on inflammasome activation, distinguishing its function in Ly6Chi monocytes from tissue-resident macrophages.

   Evidence Myeloid-specific conditional knockout with LPS and DSS colitis models and caspase-1/11 activation assays

   PMID:30487795

   Open questions at the time

   • Molecular mechanism by which COMMD10 suppresses caspase activation unknown
   • Direct inflammasome component interactions not shown
3. 2018 Medium

   Showed COMMD10 physically interacts with ENaC and positively regulates channel current, linking it to Nedd4-2 antagonism and endocytic trafficking.

   Evidence Co-IP, stable shRNA knockdown in Fischer rat thyroid epithelia, electrophysiology, and transferrin trafficking assays

   PMID:29997525

   Open questions at the time

   • Only partial functional rescue
   • Mechanistic basis of Nedd4-2 antagonism not defined
4. 2019 Medium

   Placed COMMD10 in phagolysosomal maturation via TFEB-driven lysosomal biogenesis and the CCC complex during bacterial infection.

   Evidence COMMD10-deficient macrophages/Kupffer cells, in vivo S. aureus infection, and TFEB activity assays

   PMID:30959277

   Open questions at the time

   • Direct molecular link from COMMD10 to TFEB activation not established
   • Single lab
5. 2021 Medium

   Demonstrated COMMD10 is required for homeostatic survival of tissue-resident macrophages and shapes monocyte fate during liver injury.

   Evidence Conditional knockout mice, acetaminophen liver injury, inflammasome and type I IFN assays, fate-mapping

   PMID:34788631

   Open questions at the time

   • Mechanism of survival dependence not biochemically defined
   • Causal ordering between inflammasome derepression and fate skewing unclear
6. 2022 Medium

   Identified COMMD10 as a regulator of HIF1α stability and copper homeostasis that controls ferroptosis and radiosensitivity in hepatocellular carcinoma.

   Evidence Western blot, qPCR, clonogenic radiation assays, lentivirus mouse models, and lipid peroxidation/Fe2+/Cu assays

   PMID:35101526

   Open questions at the time

   • No in vitro reconstitution or mutagenesis of the COMMD10–HIF1α interaction
   • Ubiquitin ligase involved not identified
7. 2023 Medium

   Established an essential developmental requirement for COMMD10 in neural plate and neural crest formation.

   Evidence Commd10 knockout mice with embryo phenotyping and transcriptome analysis

   PMID:36976102

   Open questions at the time

   • Mechanistic placement is transcriptomic/descriptive rather than biochemical
   • Specific COMMD10 targets driving neural crest gene loss unknown
8. 2024 Low

   Linked COMMD10 to maintenance of genomic stability through suppression of ATM-p53 signaling and support of DNA damage repair.

   Evidence Knockdown/restoration in gastric cancer cells, xenografts, and DNA damage marker/ATM-p53 assays

   PMID:38871970

   Open questions at the time

   • No direct biochemical link to DNA repair machinery
   • Single lab, KD/rescue only
9. 2025 Low

   Implicated COMMD10 as a restraint on endothelial angiogenesis and osteogenic crosstalk via the Rap1 pathway.

   Evidence Endothelial knockdown, angiogenesis assays, and RAP1B/COMMD10 double-knockdown epistasis

   PMID:40496352

   Open questions at the time

   • No direct binding assay linking COMMD10 to Rap1 components
   • Single KD approach without reconstitution

• How COMMD10's diverse roles (NF-κB, HIF1α/copper, lysosomal/TFEB, ENaC trafficking, development, DNA repair) converge on a unifying biochemical activity remains unresolved.
• No structural model of COMMD10
• Whether all functions depend on the CCC complex unknown
• Direct enzymatic or adaptor activity not defined