# ANKFY1 Gene Review Notes

## 2026-06-03 - Proteostasis PN review

ANKFY1/Rabankyrin-5 is primarily supported as a PI3P- and Rab5-associated endosomal effector. The core 2004 study identifies Rabankyrin-5 as a PI(3)P-binding Rab5 effector that localizes to early endosomes, stimulates endosomal fusion, localizes to macropinosomes, and promotes fluid-phase uptake. [PMID:15328530 "novel PI(3)P-binding Rab5 effector, Rabankyrin-5, which localises to early endosomes and stimulates their fusion activity"; PMID:15328530 "Overexpression of Rabankyrin-5 increases the number of macropinosomes and stimulates fluid-phase uptake, whereas its downregulation inhibits these processes."]

Retromer and receptor-trafficking evidence is also well supported. Zhang et al. show that Rank-5 interacts with EHD1 through the Rank-5 NPFED motif, colocalizes/interacts with retromer component VPS26, and that Rank-5 depletion disrupts mannose 6-phosphate receptor retrieval to the Golgi from endosomes and biosynthetic transport. [PMID:22284051 "binding occurs between the EH domain of EHD1 and the NPFED motif of Rank-5"; PMID:22284051 "depletion of Rank-5 causes mislocalization of Vps26 and affects both the retrieval of mannose 6-phosphate receptor transport to the Golgi from endosomes and biosynthetic transport."] RhoD work further supports a role in endosomal trafficking of activated receptor cargo. [PMID:24102721 "RhoD binds to the Rab5 effector Rabankyrin-5"; PMID:24102721 "internalization and trafficking of activated tyrosine kinase receptors."]

ANKFY1 also has direct autophagy-relevant evidence. Wei et al. identify ANKFY1 as an ATG2A-binding protein; ANKFY1 depletion impairs autophagosome growth and reduces autophagy flux; purified ANKFY1 binds PI3P through its FYVE domain and enhances ATG2A-mediated lipid transfer between PI3P-containing liposomes. [PMID:38622126 "identified a new ATG2A-binding protein, ANKFY1"; PMID:38622126 "impaired autophagosome growth and the reduced autophagy flux"; PMID:38622126 "enhanced ATG2A-mediated lipid transfer between PI3P-containing liposomes."]

PN projection assessment: the local PN projection currently proposes `GO:1990756 ubiquitin-like ligase-substrate adaptor activity` for ANKFY1 from `Ubiquitin Proteasome System > E3 ubiquitin and UBL ligases > Cul3 substrate receptor > BTB-BACK, variant > ankyrin`. This should not be propagated for ANKFY1 without gene-specific support. ANKFY1 has a BTB/POZ-related region, but the reviewed UniProt record and the ANKFY1 literature support Rab5/PI3P/endosomal trafficking and ATG2A-mediated autophagosome assembly, not validated CUL3 complex membership, substrate recognition for a ubiquitin-like ligase, or ubiquitin-like ligase-substrate adaptor activity. Curation conclusion: keep ANKFY1 as proteostasis-relevant through endosome-autophagosome lipid transfer, but exclude it from automatic UPS/Cul3 `GO:1990756` propagation unless direct CUL3-substrate-adaptor evidence is found.