ASB14

ASB14 (Ankyrin Repeat and SOCS Box Containing 14) is an E3 ubiquitin ligase that restrains cardiomyocyte proliferation and cardiac repair by targeting the microtubule-associated protein MAPRE2 for ubiquitination and proteasomal degradation (PMID:38319584). Loss of ASB14 stabilizes MAPRE2, driving cardiomyocyte nuclear proliferation and enhancing recovery of cardiac function after myocardial infarction (PMID:38319584). Conversely, ASB14 overexpression in cardiomyocytes promotes apoptosis, suppresses proliferation, and impairs mitochondrial function, acting through downstream effectors including PIP4K2A, AMPK alpha-1, and RRAGC with metabolic reprogramming in linoleic acid and purine pathways (PMID:40417864). Beyond these cardiomyocyte phenotypes, no further mechanistic detail has been characterized in the available corpus.

1. 2024 Medium

   Established ASB14 as an E3 ubiquitin ligase with a defined substrate, answering what molecular activity it carries and how it controls cardiac regeneration after injury.

   Evidence ASB14 silencing in vitro and in vivo, cardiomyocyte nuclear proliferation and cardiac function assays in ASB14-deficient mice after ischemic injury, with MAPRE2 degradation as readout

   PMID:38319584

   Open questions at the time

   • Ubiquitination of MAPRE2 was not reconstituted biochemically (no direct in vitro ligase assay)
   • Single lab; mechanism of MAPRE2 recognition by the ASB14 SOCS box / ankyrin repeats not defined
   • Whether MAPRE2 stabilization alone is sufficient for the proliferation phenotype is unresolved
2. 2025 Medium

   Defined the downstream consequences of elevated ASB14, showing it drives apoptosis and mitochondrial dysfunction and reprograms cardiomyocyte metabolism.

   Evidence ASB14 overexpression in AC16 cardiomyocytes with CCK8 proliferation, flow cytometry apoptosis, ATP measurement, TMT-iTRAQ proteomics, LC-MS/MS metabolomics, and Western validation

   PMID:40417864

   Open questions at the time

   • In vitro overexpression only; no in vivo confirmation of the metabolic/apoptotic axis
   • The listed effectors (PIP4K2A, AMPK alpha-1, RRAGC, etc.) are correlative proteomic/metabolomic hits, not validated direct targets
   • Relationship between the MAPRE2 axis and the mitochondrial/metabolic phenotype is not established

• How ASB14 physically recognizes its substrates and assembles into an E3 ligase complex, and whether its functions extend beyond cardiomyocytes, remain unknown.
• No structural model or domain-level substrate-binding mechanism
• No identification of associated E3 complex components (e.g. Cullin/Elongin partners)
• Function in non-cardiac tissues uncharacterized