COMMD2

COMMD2 is a subunit of the hetero-decameric COMMD ring within the Commander complex, where it participates in endosomal recycling of diverse transmembrane cargo and in NF-κB signaling regulation. COMMD2 was identified as one of ten COMM-domain-containing proteins that form multimeric assemblies, bind CCDC22/CCDC93, and inhibit NF-κB activity by regulating IκB ubiquitination (PMID:15799966, PMID:23563313). As part of the CCC (COMMD/CCDC22/CCDC93) complex, COMMD2 localizes to early endosomes, couples to the WASH complex and Retriever, and mediates retromer-independent recycling of >120 cell-surface proteins including integrins and the copper transporter ATP7A (PMID:25355947, PMID:28892079). Cryo-EM and X-ray crystallography resolved the position of COMMD2 within the decameric COMMD ring, revealing stabilizing interactions with the CCDC22–CCDC93 coiled-coil scaffold that bridges the CCC and Retriever sub-assemblies (PMID:37172566).

1. 2005 High

   Identification of COMMD2 as a member of a new protein family sharing the COMM domain established that, like COMMD1, it forms multimeric complexes and inhibits NF-κB, providing the first functional framework for the gene.

   Evidence Co-immunoprecipitation and NF-κB reporter assays in mammalian cells

   PMID:15799966

   Open questions at the time

   • Mechanism by which COMMD2 inhibits NF-κB not defined
   • Stoichiometry and composition of COMMD multimers unknown
   • Endogenous physiological context of NF-κB inhibition not tested
2. 2013 High

   Discovery that COMMD2 binds CCDC22—a coiled-coil protein mutated in X-linked intellectual disability—placed it within the CCC complex and connected COMMD-mediated NF-κB regulation to IκB ubiquitination and a human disease locus.

   Evidence Reciprocal co-immunoprecipitation of all COMMD proteins with CCDC22; patient-derived cell analysis; NF-κB activation assays

   PMID:23563313

   Open questions at the time

   • Direct binding interface between COMMD2 and CCDC22 not mapped
   • Whether COMMD2 individually or the full COMMD ring is required for NF-κB inhibition unclear
3. 2013 Medium

   Demonstration that COMMD2 physically interacts with ENaC expanded the repertoire of ion-channel cargo associated with COMMD proteins, though functional consequences for COMMD2 specifically were not pursued.

   Evidence Co-immunoprecipitation of COMMD2–10 with ENaC subunits in mammalian cells

   PMID:23637203

   Open questions at the time

   • Functional follow-up focused on COMMD3/9, not COMMD2
   • Whether COMMD2 regulates ENaC surface expression not tested
   • Single Co-IP without reciprocal validation for COMMD2 specifically
4. 2014 High

   Establishing that the CCC complex localizes to early endosomes, connects to the WASH complex, and is required for ATP7A recycling revealed that COMMD2 functions in endosomal cargo trafficking, not solely in NF-κB signaling.

   Evidence Affinity purification, siRNA knockdown with ATP7A trafficking readout, subcellular fractionation

   PMID:25355947

   Open questions at the time

   • Individual contribution of COMMD2 versus other COMMD subunits to trafficking not distinguished
   • Structural basis of CCC–WASH coupling unknown at this point
5. 2017 High

   Identification of the Commander supercomplex (CCC + Retriever + SNX17) and quantitative surface proteomics showing retromer-independent recycling of >120 cargo proteins defined the major physiological role of COMMD2 as part of a broad endosomal recycling machine.

   Evidence AP-MS, quantitative surface proteomics, siRNA knockdown with integrin recycling assays

   PMID:28892079

   Open questions at the time

   • Whether COMMD2 has cargo-specific roles within the Commander complex not addressed
   • Mechanism by which Commander selects individual cargo unknown
6. 2023 High

   Cryo-EM and X-ray crystallography resolved the complete Commander structure, placing COMMD2 at a defined position in the hetero-decameric COMMD ring and revealing how the CCDC22–CCDC93 coiled-coil scaffold bridges CCC to Retriever.

   Evidence Cryo-EM, X-ray crystallography, mutagenesis validation

   PMID:37172566

   Open questions at the time

   • Conformational dynamics of the COMMD ring during cargo engagement not captured
   • Whether COMMD2 directly contacts any cargo or adaptor remains unknown
7. 2022 Medium

   Knockdown of COMMD2 inhibited proliferation and migration in bladder and endometrial cancer cells, with pathway enrichment implicating E2F targets and the G2/M checkpoint, suggesting COMMD2 supports cell-cycle progression in proliferative contexts.

   Evidence siRNA knockdown; CCK-8, EdU, wound healing, and transwell assays in BLCA and UCEC cell lines; GSEA

   PMID:36205192

   Open questions at the time

   • Not independently replicated in a second laboratory
   • Whether proliferation effects are Commander-dependent or reflect a COMMD2-specific moonlighting function is unknown
   • Mechanism linking COMMD2 to E2F/G2M pathways not defined

• Whether COMMD2 has non-redundant functions within the hetero-decameric COMMD ring—e.g., cargo-specific recruitment or position-dependent allosteric roles—remains an open question.
• No single-subunit deletion/replacement experiment for COMMD2 within the intact ring
• No direct cargo-binding data for COMMD2
• Tissue-specific in vivo phenotype of COMMD2 loss not characterized