ANKRD13A

ANKRD13A is a ubiquitin-interacting-motif (UIM) scaffold protein that selectively recognizes Lys-63-linked polyubiquitin chains on diverse membrane and signaling substrates to direct VCP/p97-dependent membrane remodeling and trafficking (PMID:26797118, PMID:40975168). Through its UIMs it binds ubiquitinated Caveolin-1 and assembles a ternary complex with VCP/p97 on endosomal membranes to route Cav-1 oligomers for lysosomal trafficking (PMID:26797118), and it cooperates with the E3 ligase RNF11 and the ITCH-dependent ubiquitination of ANKRD13A itself to gate binding to activated EGFR and its sorting toward lysosomal degradation (PMID:31985874). Upon PINK1/Parkin-driven mitochondrial depolarization, ANKRD13A relocates to depolarized mitochondria and recruits VCP/p97 to the outer membrane to promote membrane rupture required for mitophagy (PMID:40975168), and it is similarly recruited to ubiquitinated Toxoplasma parasitophorous vacuoles with VCP/p97 and UBXD1 to drive their acidification and restrict the parasite (PMID:37975677). Beyond trafficking, ANKRD13A binds ubiquitinated RIP1 within TNF complex-II via its UIM and limits FADD/caspase-8 recruitment, raising the threshold for TNF-induced apoptosis without affecting NF-κB activation (PMID:34839354).

1. 2016 High

   Established ANKRD13A's core biochemical activity: that its UIMs read Lys-63-linked polyubiquitin and couple a ubiquitinated cargo (Cav-1) to VCP/p97 for lysosomal delivery, defining it as a ubiquitin-selective trafficking adaptor.

   Evidence Co-IP, MS ubiquitin-linkage analysis, UIM-deletion mutagenesis and overexpression phenotypes (enlarged late endosomes) in cells, including IBMPFD VCP mutants

   PMID:26797118

   Open questions at the time

   • No structural model of UIM–Lys63-Ub recognition
   • Whether VCP recruitment is direct or bridged by additional cofactors not resolved
2. 2020 High

   Extended the adaptor role to receptor tyrosine kinase sorting and showed ANKRD13A's own ubiquitination state is a regulatory switch, governed by ITCH and RNF11, for binding activated EGFR.

   Evidence SILAC Co-IP proteomics, UIM-deletion mutants, EGF time-course, and RNAi of ITCH and RNF11 with ubiquitination readouts

   PMID:31985874

   Open questions at the time

   • Site(s) of ANKRD13A ubiquitination not mapped
   • Functional consequence for EGFR degradation kinetics in vivo not quantified
3. 2021 High

   Identified a death-signaling function distinct from trafficking: ANKRD13A binds ubiquitinated RIP1 in TNF complex-II to limit FADD/caspase-8 assembly, positioning it as a checkpoint balancing survival versus apoptosis.

   Evidence Co-IP with ubiquitinated RIP1, complex-II assembly assays, knockout/knockdown with TNF death and NF-κB reporter readouts, UIM-dependent interaction studies

   PMID:34839354

   Open questions at the time

   • Whether VCP/p97 participates in the complex-II function not addressed
   • Linkage type of RIP1 ubiquitin recognized not directly defined here
4. 2023 Medium

   Showed the ANKRD13A–VCP module is deployed in cell-autonomous immunity, recruited to ubiquitinated pathogen vacuoles to drive their acidification.

   Evidence Knockdown/knockout parasite restriction assay, immunofluorescence localization to ubiquitinated PVs, IFNγ stimulation, co-depletion epistasis with p97/VCP and UBXD1

   PMID:37975677

   Open questions at the time

   • Single study
   • Direct biochemical demonstration of ANKRD13A binding PV ubiquitin not shown
5. 2025 High

   Demonstrated ANKRD13A drives mitochondrial outer-membrane rupture during mitophagy by recruiting VCP/p97 to depolarized mitochondria, generalizing its VCP-recruiting trafficking role to organelle quality control.

   Evidence Live-cell OMM-rupture biosensor imaging, localization on depolarized mitochondria, Co-IP with mitochondrial proteins, loss-of-function with mitophagy/OMM-rupture readouts

   PMID:40975168

   Open questions at the time

   • Identity of the ubiquitinated OMM substrate(s) read by ANKRD13A not defined
   • Relationship to other VCP mitophagy cofactors not delineated
6. 2021 Low

   Implicated ANKRD13A in tumor immune evasion by promoting Lys-63-Ub-dependent internalization of HLA class I, downstream of lncRNA-driven chromatin activation.

   Evidence USP30-AS1 perturbation, ANKRD13A knockdown, cell-surface HLA-I flow/imaging, ChIP for histone marks in AML cells

   PMID:34694569

   Open questions at the time

   • Direct ANKRD13A–Lys63-Ub–HLA-I interaction not biochemically validated
   • Mechanism inferred largely from functional readouts
   • Single lab
7. 2013 Medium

   Earliest functional link, placing Ankrd13A downstream of miR-204 in regulating focal adhesion dynamics and lens/neural crest morphogenesis.

   Evidence Morpholino miR-204 knockdown and Ankrd13A overexpression with live imaging in medaka, focal adhesion assays, 3'UTR reporter, in vivo rescue

   PMID:23620728

   Open questions at the time

   • Direct biochemical role of ANKRD13A in focal adhesion regulation unresolved
   • Connection to its ubiquitin-trafficking activity not established

• How ANKRD13A discriminates among its many ubiquitinated substrates and is targeted to specific membranes/complexes in a context-dependent manner remains unresolved.
• No structural basis for substrate/linkage selectivity
• Determinants of subcellular targeting across endosomes, mitochondria, vacuoles, and complex-II not defined
• Whether a unifying VCP-handoff mechanism operates across all contexts unknown