Annotation inferences using phylogenetic trees

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

file:human/UBAC2/UBAC2-hypotheses/function-hypothesis-go-0004252/openscientist.md

OpenScientist hypothesis investigation - UBAC2 serine-type endopeptidase activity

OpenScientist refuted the UBAC2 GO:0004252 serine-type endopeptidase activity hypothesis and recommended removing the propagated IBA annotation.

"UBAC2 does not have serine-type endopeptidase activity (GO:0004252). The annotation should be removed."
The report traced the incorrect IBA to phylogenetic transfer from active rhomboid proteases to a catalytically inactive rhomboid pseudoprotease.

"The IBA (Inferred from Biological Ancestor) annotation originated from PANTHER phylogenetic propagation (GO_REF:0000033), which incorrectly transferred serine endopeptidase activity from active rhomboid proteases to UBAC2 based on family membership alone."
The report identifies a GSSG motif only at residues 6-9, outside annotated membrane spans, and no membrane catalytic histidine; primary PMID:23297223 independently calls UBAC2 an ER-resident rhomboid pseudoprotease. This supports loss of proteolysis while trafficking and ER-phagy remain valid.

"No GxSG motif exists within the three transmembrane segments of UBAC2"

PMID:22119785

Defining human ERAD networks through an integrative mapping strategy.

UBAC2 interacts with FAF2/UBXD8 within the human ERAD interaction network.

PMID:23297223

Spatial regulation of UBXD8 and p97/VCP controls ATGL-mediated lipid droplet turnover.

UBAC2 is an ER-resident rhomboid pseudoprotease that acts as a selective FAF2/UBXD8 ER receptor, restricting trafficking of FAF2 from the ER to lipid droplets.

PMID:25416956

A proteome-scale map of the human interactome network.

PMID:25660456

Identification of ERAD components essential for dislocation of the null Hong Kong variant of α-1-antitrypsin (NHK).

ERAD requires dislocation/retrotranslocation of substrates from the ER lumen to the cytosol; UBAC2 negatively regulates this dislocation step.

PMID:28514442

Architecture of the human interactome defines protein communities and disease networks.

PMID:31073040

LMBR1L regulates lymphopoiesis through Wnt/β-catenin signaling.

UBAC2 (with LMBR1L and AMFR) attenuates canonical Wnt/beta-catenin signaling in lymphocytes by promoting degradation of CTNNB1 and Wnt receptors FZD6/LRP6.

PMID:39284914

ER-phagy restrains inflammatory responses through its receptor UBAC2.

UBAC2 is a receptor for ER-phagy and a negative regulator of inflammatory responses; its LIR motif binds GABARAP and MARK2-mediated Ser223 phosphorylation drives dimerization to facilitate selective ER degradation.

PMID:40205054

Multimodal cell maps as a foundation for structural and functional genomics.

PMID:22455605

Replication study confirms the association between UBAC2 and Behçet's disease in two independent Chinese sets of patients and controls.

UBAC2 is a confirmed Behçet's disease susceptibility locus in Han Chinese; the risk T allele of promoter SNP rs3825427 has lower promoter activity and is associated with decreased expression of UBAC2 transcript variant 1, implicating transcriptional modulation of UBAC2 in disease risk.

PMID:21700618

Genome-wide association study identifies novel alleles associated with risk of cutaneous basal cell carcinoma and squamous cell carcinoma.

A variant (rs7335046) at the 13q32 locus near UBAC2 confers susceptibility to cutaneous basal cell carcinoma and squamous cell carcinoma.

file:human/UBAC2/UBAC2-uniprot.txt

UniProt entry Q8NBM4 (UBAC2_HUMAN), ubiquitin-associated domain-containing protein 2

UBAC2 is a multi-pass ER membrane rhomboid pseudoprotease with a cytoplasmic UBA domain; it is an ER-phagy receptor (LIR/GABARAP), restricts FAF2 trafficking to lipid droplets, and negatively regulates canonical Wnt signaling with LMBR1L and AMFR.

file:human/UBAC2/UBAC2-deep-research-falcon.md

Falcon research report for human UBAC2

The report highlights the 2024 LIR-GABARAP ER-phagy mechanism; this was checked against primary PMID:39284914 before specifying adaptor activity.

"UBAC2 contains a **canonical LIR** in its cytosolic domain that binds **GABARAP**."