ANKRD53

ANKRD53 is an ankyrin repeat scaffold protein with distinct roles in mitotic spindle regulation and adipocyte lipid metabolism (PMID:26820536, PMID:41654016). In mitosis, it was identified as a DDA3-interacting protein that is recruited to the mitotic spindle by DDA3 (PMID:26820536), where it functionally antagonizes DDA3 to control spindle microtubule polymerization (PMID:26820536); its depletion delays mitotic progression, produces unaligned chromosomes, reduces spindle MT polymerization, activates the spindle assembly checkpoint, and causes bi-nucleate and polylobed nuclei, indicating a requirement for proper chromosome alignment and cytokinesis (PMID:26820536). In adipocytes, ANKRD53 binds ACSL1 and promotes its mitochondrial localization, thereby channeling lipolysis-derived free fatty acids into β-oxidation; loss of ACSL1 abolishes ANKRD53's metabolic effects (PMID:41654016), and ANKRD53 levels bidirectionally regulate forskolin-stimulated lipolysis and mitochondrial respiration in human primary adipocytes and in mouse adipose tissue (PMID:41654016). Beyond these two contexts, no further mechanistic detail has been characterized in the available corpus.

1. 2016 Medium

   Established ANKRD53 as a spindle-associated factor by identifying it as a DDA3 interactor recruited to the mitotic spindle, defining a starting point for its mitotic function.

   Evidence Co-IP/mass spectrometry and subcellular localization in cultured cells

   PMID:26820536

   Open questions at the time

   • Interaction domain and the structural basis of DDA3-mediated recruitment not mapped
   • Whether the DDA3 interaction is direct not established
2. 2016 Low

   Indicated ANKRD53 is a mitotic phosphoprotein, hinting at regulation by cell-cycle kinases.

   Evidence Expression and phosphorylation profiling across mitotic progression

   PMID:26820536

   Open questions at the time

   • No responsible kinase identified
   • No phosphosite mapping or mutagenesis
   • Functional consequence of phosphorylation unknown
3. 2016 Medium

   Defined the functional requirement of ANKRD53 in mitosis, showing it is needed for chromosome alignment, spindle MT polymerization, SAC silencing, and faithful cytokinesis.

   Evidence siRNA knockdown in HeLa cells with multiple mitotic phenotype readouts

   PMID:26820536

   Open questions at the time

   • Mechanism by which ANKRD53 promotes MT polymerization unknown
   • Single-lab, single-cell-line evidence
   • No rescue with wild-type vs mutant constructs reported
4. 2016 Medium

   Resolved the apparent paradox of co-localization by showing ANKRD53 antagonizes DDA3 in spindle MT polymerization, placing the two proteins in opposition within one pathway.

   Evidence Genetic epistasis/functional comparison of DDA3 and ANKRD53 knockdowns with spindle readouts

   PMID:26820536

   Open questions at the time

   • Molecular basis of antagonism not defined
   • Whether antagonism involves competition for a shared effector unknown
5. 2026 Medium

   Revealed an unrelated metabolic function, demonstrating ANKRD53 bidirectionally controls lipolysis and mitochondrial respiration in adipocytes in vitro and in vivo.

   Evidence Overexpression/knockdown in human primary adipocytes (FFA/glycerol release, OCR) and AAV overexpression in mouse iWAT

   PMID:41654016

   Open questions at the time

   • Single-lab evidence
   • Connection, if any, between mitotic and metabolic roles unestablished
6. 2026 Medium

   Provided the mechanism for the metabolic effect, showing ANKRD53 binds ACSL1 and drives its mitochondrial localization to couple FFA release to β-oxidation.

   Evidence IP-MS interactor identification, ACSL1 subcellular localization, and ACSL1 knockdown epistasis

   PMID:41654016

   Open questions at the time

   • Whether ANKRD53-ACSL1 binding is direct not shown
   • ANKRD53 domain mediating ACSL1 binding/mitochondrial targeting not mapped

• Whether the mitotic spindle role and the adipocyte metabolic role reflect a unifying scaffold mechanism, and how ANKRD53 is regulated across these contexts, remains unresolved.
• No structural model of ANKRD53
• No shared interactor connecting spindle and metabolic functions
• Tissue-specific expression and regulation not characterized