GO Term	Evidence	Action	Reason
GO:0004252 serine-type endopeptidase activity	IBA GO_REF:0000033	REMOVE	Summary: UBAC2 belongs to the rhomboid superfamily but is a catalytically inactive pseudoprotease; the UniProt record and ERAD literature describe it as a rhomboid pseudoprotease lacking the serine-protease catalytic dyad. This IBA is propagated from the active-rhomboid branch of the phylogenetic tree and is biologically incorrect for UBAC2. Reason: UBAC2 is a rhomboid pseudoprotease with no protease activity; the serine-type endopeptidase activity is an over-propagated phylogenetic inference refuted on biological grounds (no catalytic residues). OpenScientist independently refuted the activity assignment and traced it to transfer from active rhomboid proteases. Propagation Review Root cause: PROPAGATION BAD Failure modes: WRONG ORTHOLOG OR PARALOG PSEUDO OR SUBACTIVITY LOSS Sources checked: GO_REF:0000033 · PAINT phylogenetic IBA inference SUPPORTS SOURCE BUT NOT TARGET The family-level inference transfers serine endopeptidase activity from active rhomboid proteases, but UBAC2 is a rhomboid pseudoprotease lacking the catalytic residues and topology needed for protease activity. Supporting Evidence: PMID:23297223 the ER-resident rhomboid pseudoprotease UBAC2 file:human/UBAC2/UBAC2-hypotheses/function-hypothesis-go-0004252/openscientist.md UBAC2 does not have serine-type endopeptidase activity (GO:0004252). The annotation should be removed. file:human/UBAC2/UBAC2-hypotheses/function-hypothesis-go-0004252/openscientist.md 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.
GO:0005789 endoplasmic reticulum membrane	IEA GO_REF:0000044	ACCEPT	Summary: UBAC2 is a multi-pass ER membrane protein; the electronic subcellular-location assignment is consistent with direct experimental evidence. Reason: Core compartment; UBAC2 is an integral ER membrane protein. Supporting Evidence: file:human/UBAC2/UBAC2-uniprot.txt SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
GO:0005515 protein binding	IPI PMID:22119785 Defining human ERAD networks through an integrative mapping ...	KEEP AS NON CORE	Summary: ERAD-network interactome capture of the UBAC2-FAF2 interaction. The bare protein binding term is uninformative; the functional relationship is captured by the FAF2/ER-receptor annotations. Reason: Real ERAD-network interaction (FAF2) but uninformative GO term. Supporting Evidence: file:human/UBAC2/UBAC2-uniprot.txt Q8NBM4; Q96CS3: FAF2
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	KEEP AS NON CORE	Summary: Proteome-scale interactome capture (CALCOCO2). Bare protein binding is uninformative. Reason: Real interaction from a large-scale interactome but uninformative GO term. Supporting Evidence: file:human/UBAC2/UBAC2-uniprot.txt Q8NBM4; Q13137: CALCOCO2
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	KEEP AS NON CORE	Summary: High-throughput interactome capture of the UBAC2-FAF2 interaction. Bare protein binding is uninformative. Reason: Real interaction (FAF2) but uninformative GO term. Supporting Evidence: file:human/UBAC2/UBAC2-uniprot.txt Q8NBM4; Q96CS3: FAF2
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	KEEP AS NON CORE	Summary: Multimodal cell-map interactome capture of the UBAC2-FAF2 interaction. Bare protein binding is uninformative. Reason: Real interaction (FAF2) but uninformative GO term. Supporting Evidence: file:human/UBAC2/UBAC2-uniprot.txt Q8NBM4; Q96CS3: FAF2
GO:0090090 negative regulation of canonical Wnt signaling pathway	IEA GO_REF:0000107	ACCEPT	Summary: Orthology-based assignment of the negative Wnt-regulation role, consistent with the experimental IMP evidence (LMBR1L/AMFR complex promotes degradation of CTNNB1 and Wnt receptors). Reason: Correct biological process; redundant with experimental IMP evidence. Supporting Evidence: PMID:31073040 attenuated Wnt signaling in lymphocytes
GO:0005515 protein binding	IPI PMID:39284914 ER-phagy restrains inflammatory responses through its recept...	KEEP AS NON CORE	Summary: IPI interactions from the ER-phagy study (including GABARAP-family/autophagy partners). Bare protein binding is uninformative; the GABARAP binding underpins the ER-phagy receptor function captured by the reticulophagy annotation. Reason: Real autophagy-partner interactions but uninformative GO term. Supporting Evidence: PMID:39284914 binds to autophagosomal GABARAP
GO:0050728 negative regulation of inflammatory response	IMP PMID:39284914 ER-phagy restrains inflammatory responses through its recept...	ACCEPT	Summary: By driving ER-phagy, UBAC2 restrains ER-stress-induced inflammatory responses and acute colitis in mice; perturbation of UBAC2 alters the inflammatory response. Reason: Directly supported (IMP); a downstream consequence of UBAC2's ER-phagy receptor activity. Supporting Evidence: PMID:39284914 UBAC2 restrains inflammatory responses and acute ulcerative
GO:0061709 reticulophagy	IMP PMID:39284914 ER-phagy restrains inflammatory responses through its recept...	ACCEPT	Summary: UBAC2 is a selective ER-phagy (reticulophagy) receptor with a LIR motif that binds GABARAP; MARK2-mediated Ser223 phosphorylation drives dimerization and GABARAP binding to mediate selective ER degradation. Reason: Directly demonstrated core biological process; UBAC2 functions as an ER-phagy receptor. Supporting Evidence: PMID:39284914 we identified ubiquitin-associated domain-containing protein 2 (UBAC2) as a receptor for ER-phagy
GO:0005515 protein binding	IPI PMID:31073040 LMBR1L regulates lymphopoiesis through Wnt/β-catenin signali...	KEEP AS NON CORE	Summary: IPI capture of the UBAC2-LMBR1L interaction. Bare protein binding is uninformative; the functional cooperation is captured by the negative Wnt-regulation annotation. Reason: Real interaction (LMBR1L) but uninformative GO term. Supporting Evidence: file:human/UBAC2/UBAC2-uniprot.txt Interacts with LMBR1L
GO:0090090 negative regulation of canonical Wnt signaling pathway	IMP PMID:31073040 LMBR1L regulates lymphopoiesis through Wnt/β-catenin signali...	ACCEPT	Summary: With LMBR1L and AMFR, UBAC2 negatively regulates canonical Wnt signaling in lymphocytes by promoting ubiquitin-mediated degradation of CTNNB1 and the Wnt receptors FZD6 and LRP6. Reason: Directly supported (IMP) biological process; a distinct UBAC2 regulatory role. Supporting Evidence: PMID:31073040 attenuated Wnt signaling in lymphocytes
GO:1904153 negative regulation of retrograde protein transport, ER to cytosol	IMP PMID:25660456 Identification of ERAD components essential for dislocation ...	ACCEPT	Summary: UBAC2 negatively regulates ER-to-cytosol dislocation/retrotranslocation, consistent with its role as the ER receptor that restricts FAF2/UBXD8 trafficking and modulates ERAD substrate dislocation. Reason: Directly supported (IMP); UBAC2 modulates the ER-to-cytosol retrotranslocation step of ERAD. Supporting Evidence: PMID:25660456 dislocation, also known as retrotranslocation, of those unwanted proteins from
GO:0005783 endoplasmic reticulum	IDA PMID:23297223 Spatial regulation of UBXD8 and p97/VCP controls ATGL-mediat...	ACCEPT	Summary: Direct evidence that UBAC2 is an ER-resident protein, the compartment where it acts as an ER receptor for FAF2/UBXD8. Reason: Core compartment; directly demonstrated. Supporting Evidence: PMID:23297223 the ER-resident rhomboid pseudoprotease UBAC2
GO:0070972 protein localization to endoplasmic reticulum	IDA PMID:23297223 Spatial regulation of UBXD8 and p97/VCP controls ATGL-mediat...	ACCEPT	Summary: UBAC2 retains FAF2/UBXD8 at the ER (restricting its trafficking to lipid droplets), thereby controlling FAF2 protein localization to the ER. Reason: Directly supported; UBAC2 acts as an ER receptor that governs partner localization at the ER. Supporting Evidence: PMID:23297223 restricts trafficking of UBXD8 to LDs

Deep Research

Falcon

(UBAC2-deep-research-falcon.md)

Comprehensive Research Report: Human **UBAC2** (UniProt **Q8NBM4**) — Functional Annotation, Pathways, and Disease Context Falcon Edison Scientific Literature 34 citations 2 artifacts 2026-06-12T05:08:23.141621

Edison artifact artifact-00 (text/markdown)

## Context ID: pqac-00000021 Figure 3 and the relevant panels are provided: - Figure 3A-C: Schematic of the ss-RFP-GFP-KDEL reporter and quantification of ER-ph (image/png)

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

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Comprehensive Research Report: Human UBAC2 (UniProt Q8NBM4) — Functional Annotation, Pathways, and Disease Context

Executive summary

UBAC2 (UBA domain–containing protein 2; UniProt Q8NBM4; synonym PHGDHL1) encodes an ER-resident, rhomboid-like multi-pass membrane pseudoprotein with a cytosolic ubiquitin-associated (UBA) domain that has been historically linked to ER-associated degradation (ERAD) and ubiquitin-dependent protein quality control (proteostasis). (adrain2020thecomplexlife pages 15-18, kandel2020theroleof pages 10-14, lemberg2016inactiverhomboidproteins pages 16-21, choi2019lmbr1lregulateslymphopoiesis pages 1-2)

A major 2024 advance is the discovery that UBAC2 also functions as a selective autophagy receptor for ER-phagy (reticulophagy): it binds GABARAP via a cytosolic LC3-interacting region (LIR) and is activated by MARK2 phosphorylation at S223, which promotes UBAC2 dimerization and increased GABARAP binding. This UBAC2-driven ER-phagy restrains ER stress/UPR-linked inflammation and protects against DSS-induced colitis in vivo. (he2024erphagyrestrainsinflammatory pages 1-2, he2024erphagyrestrainsinflammatory pages 12-13, he2024erphagyrestrainsinflammatory pages 15-16, he2024erphagyrestrainsinflammatory pages 7-8)

1. Key concepts and definitions (current understanding)

1.1 UBAC2 as a rhomboid-like “pseudoprotease”

“Rhomboid-like” proteins share a rhomboid fold (typically multiple transmembrane helices) but may lack protease activity; such proteins are often termed rhomboid pseudoproteases and can act as adapters/scaffolds that regulate client protein trafficking, turnover, and signaling rather than catalyzing proteolysis. Reviews place UBAC2 within this class and connect rhomboid-like factors to ER protein quality control. (lemberg2016inactiverhomboidproteins pages 16-21, adrain2020thecomplexlife pages 1-5)

1.2 UBA domain and ubiquitin-dependent protein quality control

UBA (ubiquitin-associated) domains are small protein modules that can bind ubiquitin or polyubiquitin chains and thereby link proteins to ubiquitin signaling and degradation pathways. Reviews specifically describe UBAC2 as having a conserved C-terminal UBA domain that binds polyubiquitin chains, consistent with an adapter role in ubiquitin-dependent quality control. (kandel2020theroleof pages 10-14, lemberg2016inactiverhomboidproteins pages 16-21)

1.3 ERAD (endoplasmic reticulum–associated degradation)

ERAD is a canonical ER quality-control process in which misfolded or orphaned ER proteins are recognized, ubiquitinated, extracted (often via the p97/VCP machinery), and degraded by the proteasome. Reviews place UBAC2 within ERAD-related networks (including the GP78 pathway) and highlight its interactions with UBXD8/p97 axis components relevant to substrate processing. (adrain2020thecomplexlife pages 15-18, kandel2020theroleof pages 10-14, lemberg2016inactiverhomboidproteins pages 16-21)

1.4 ER-phagy (reticulophagy) and LIR–ATG8 family interactions

ER-phagy is selective autophagic degradation of ER fragments. ER-phagy receptors often contain a LIR motif that binds ATG8-family proteins (e.g., GABARAP/LC3) to couple ER membranes to autophagosomes. In 2024, UBAC2 was shown to be such a receptor via its cytosolic LIR and GABARAP binding. (he2024erphagyrestrainsinflammatory pages 1-2, he2024erphagyrestrainsinflammatory pages 12-13, he2024erphagyrestrainsinflammatory pages 7-8)

2. Molecular identity verification (critical disambiguation)

The literature sources retrieved here consistently describe human UBAC2 as “ubiquitin-associated domain–containing protein 2,” and genetic studies explicitly note that PHGDHL1 is alternatively called UBAC2, supporting the UniProt synonym set and mitigating symbol ambiguity. (nan2011genomewideassociationstudy pages 1-2, hou2012replicationstudyconfirms pages 1-2)

3. Protein features, localization, and primary molecular functions

3.1 Subcellular localization

Multiple sources place UBAC2 at the endoplasmic reticulum (ER).

Primary evidence (pathway study): An “ER-localized LMBR1L-GP78-UBAC2 complex” is reported to regulate degradation of Wnt pathway components. (choi2019lmbr1lregulateslymphopoiesis pages 1-2)
Primary evidence (ER-phagy study): UBAC2 is described as residing at the ER and functioning as an ER-phagy receptor; ER stress/starvation induces UBAC2 relocalization/turnover consistent with autophagy/lysosomal routing. (he2024erphagyrestrainsinflammatory pages 12-13, he2024erphagyrestrainsinflammatory pages 3-4)

3.2 UBAC2 as an ER-phagy receptor (major 2024 development)

A 2024 EMBO Journal study provides direct mechanistic evidence that UBAC2 is an ER-phagy receptor.

Core mechanism
* UBAC2 contains a canonical LIR in its cytosolic domain that binds GABARAP. (he2024erphagyrestrainsinflammatory pages 1-2, he2024erphagyrestrainsinflammatory pages 12-13)
* Under ER stress or autophagy activation, MARK2 phosphorylates UBAC2 at S223, promoting UBAC2 dimerization and stronger GABARAP binding, thereby enhancing ER-phagy. (he2024erphagyrestrainsinflammatory pages 1-2, he2024erphagyrestrainsinflammatory pages 12-13)

Experimental readouts and quantitative design features
* ER-phagy flux was monitored with an ER luminal reporter ss-RFP-GFP-KDEL, in which lysosomal delivery quenches GFP and yields an RFP fragment; UBAC2 knockout reduces reporter processing under starvation conditions, while UBAC2 WT rescues and a LIR mutant (LIRm) fails to rescue. (he2024erphagyrestrainsinflammatory pages 7-8)
* Quantification in microscopy includes 20 cells scored/condition and statistics reported across 3 biological replicates (mean ± SEM). (he2024erphagyrestrainsinflammatory pages 12-13)

Physiological/in vivo implications
* In a DSS acute ulcerative colitis mouse model, AAV-mediated expression of UBAC2 variants (WT vs LIRm vs S223A and disease-associated variants) was tested with n = 6 mice/group and multiple outcome measures including body weight, colon length, histology, and qPCR markers of ER stress and inflammation. (he2024erphagyrestrainsinflammatory pages 15-16)
* The study concludes that UBAC2-mediated ER-phagy restrains inflammatory responses and protects against colitis pathology. (he2024erphagyrestrainsinflammatory pages 1-2, he2024erphagyrestrainsinflammatory pages 15-16)

Figure-level support
Cropped panels of Figure 3 directly show: the ER-phagy reporter concept and quantification; rescue by UBAC2 WT but not LIRm; immunoblot readouts under starvation; and UBAC2–GABARAP co-immunoprecipitation. (he2024erphagyrestrainsinflammatory media 2051f18f, he2024erphagyrestrainsinflammatory media 4a49bd3c, he2024erphagyrestrainsinflammatory media 87f2e417, he2024erphagyrestrainsinflammatory media a2146745)

3.3 UBAC2 in ERAD-like ubiquitin-mediated degradation and Wnt pathway attenuation

Prior to 2024, UBAC2’s best-supported mechanistic placement was in ER-associated ubiquitin-dependent quality control.

A 2019 Science study reports that UBAC2 participates in an “ER-localized LMBR1L-GP78-UBAC2 complex” that promotes ubiquitin-mediated degradation of Wnt receptors (e.g., FZD and LRP6) and helps attenuate Wnt/β-catenin signaling in lymphocytes. (choi2019lmbr1lregulateslymphopoiesis pages 1-2)
Reviews integrate UBAC2 into the broader ERAD conceptual framework, discussing its interactions with ubiquitin-binding modules and ERAD components (including association with UBXD8/p97-related machinery and GP78-linked pathways). (adrain2020thecomplexlife pages 15-18, kandel2020theroleof pages 10-14, lemberg2016inactiverhomboidproteins pages 16-21)

4. Recent developments and latest research (prioritize 2023–2024)

4.1 2024: UBAC2–MARK2 axis links ER stress to ER-phagy and inflammation

The central 2024 discovery is that UBAC2 is a regulated ER-phagy receptor, with an explicit upstream kinase (MARK2) and a defined regulatory site (S223 phosphorylation) that modulates receptor activity through dimerization and strengthened GABARAP binding. (he2024erphagyrestrainsinflammatory pages 1-2, he2024erphagyrestrainsinflammatory pages 12-13)

4.2 2023: UBAC2 in updated ER quality-control frameworks

A 2023 Cold Spring Harbor Perspectives in Biology review summarizes the roles of rhomboid superfamily members in ER protein quality control and includes UBAC2 within this proteostasis context, providing a recent synthesis that anticipates why a rhomboid-like ER membrane factor may integrate multiple quality-control outputs (e.g., ubiquitin pathways and autophagy). (OpenTargets Search: -UBAC2)

5. Current applications and real-world implementations

5.1 Translational hypothesis generation: inflammation and IBD

Because UBAC2-driven ER-phagy restrains ER stress/UPR-linked inflammation and mitigates colitis phenotypes in vivo (DSS model), the UBAC2–MARK2–GABARAP axis provides a mechanistically grounded target pathway for therapeutic exploration in inflammatory disease contexts where ER stress contributes to pathology. (he2024erphagyrestrainsinflammatory pages 1-2, he2024erphagyrestrainsinflammatory pages 15-16)

5.2 Signaling pathway modulation: Wnt/β-catenin brake

The LMBR1L–GP78–UBAC2 complex was proposed as a second “brake” on Wnt signaling in lymphocytes by promoting ER-localized ubiquitination and degradation of Wnt receptors and β-catenin, suggesting a potential lever for contexts where Wnt signaling needs to be constrained. (choi2019lmbr1lregulateslymphopoiesis pages 1-2)

5.3 Human genetics and biomarker context

UBAC2 is implicated as a susceptibility locus across several diseases by genetics and aggregated evidence.

Behçet’s disease: Fine-mapped promoter variants modulate UBAC2 transcription, supporting a plausible regulatory mechanism for disease risk. (hou2012replicationstudyconfirms pages 4-5, hou2012replicationstudyconfirms pages 5-6, hou2012replicationstudyconfirms pages 1-2)
Skin cancers: The UBAC2 region shows genome-wide significant associations with basal cell carcinoma risk, suggesting clinical relevance as a locus (while not proving causality of UBAC2 protein function). (nan2011genomewideassociationstudy pages 1-2)
Database aggregation: Open Targets lists UBAC2 associations with asthma, psoriasis, actinic keratosis, hypothyroidism, etc., which is useful for target prioritization and hypothesis generation. (OpenTargets Search: -UBAC2)

6. Expert synthesis and analysis (authoritative interpretations)

6.1 UBAC2 as an integrator of ER proteostasis pathways

Across authoritative reviews, UBAC2 is repeatedly positioned as an ER membrane rhomboid-like factor with a ubiquitin-binding UBA module that participates in ER quality control, including ERAD-linked networks and lipid-droplet related trafficking (via UBXD8). (adrain2020thecomplexlife pages 15-18, kandel2020theroleof pages 10-14, lemberg2016inactiverhomboidproteins pages 16-21)

The 2024 identification of UBAC2 as an ER-phagy receptor provides a coherent functional extension: UBAC2 appears capable of routing ER components to both proteasome-associated and autophagy-associated disposal pathways depending on stress context and regulatory state (e.g., MARK2 phosphorylation), consistent with modern views that ER proteostasis involves coordinated and partially redundant degradation systems. (he2024erphagyrestrainsinflammatory pages 1-2, he2024erphagyrestrainsinflammatory pages 12-13)

6.2 Caution on mechanistic specificity vs locus association

Genetic associations at the UBAC2/PHGDHL1 locus (e.g., skin cancer GWAS) establish medical relevance but do not alone demonstrate UBAC2 as the causal gene or define causal mechanisms; mechanistic interpretation should primarily rely on direct experiments such as the 2019 Science and 2024 EMBO Journal studies. (nan2011genomewideassociationstudy pages 1-2, choi2019lmbr1lregulateslymphopoiesis pages 1-2, he2024erphagyrestrainsinflammatory pages 1-2)

7. Relevant statistics and data (selected)

7.1 Behçet’s disease (Chinese Han cohorts) — UBAC2 locus

In a two-stage study totaling 477 BD cases and 1,334 controls, UBAC2 showed replicated association, including (selected examples):

rs3825427: combined Pc = 6.9 × 10^-6, OR = 1.5; promoter risk T allele had lower promoter activity than G allele (P = 0.002) and was associated with decreased UBAC2 transcript variant 1 expression in PBMCs and skin (Bonferroni-corrected P = 0.045 and P = 0.025). (hou2012replicationstudyconfirms pages 4-5, hou2012replicationstudyconfirms pages 5-6)
rs9517668: combined Pc = 3.3 × 10^-4, OR = 1.4. (hou2012replicationstudyconfirms pages 4-5)
rs9517701: combined Pc = 2.9 × 10^-5, OR = 1.4. (hou2012replicationstudyconfirms pages 4-5)

7.2 Skin cancer GWAS (UBAC2 region)

For basal cell carcinoma (BCC), rs7335046 near UBAC2 showed combined OR 1.26 (95% CI 1.18–1.34) with P = 2.9 × 10^-8 (genome-wide significant) in a discovery + replication GWAS design. (nan2011genomewideassociationstudy pages 1-2)

7.3 2024 ER-phagy functional statistics (selected)

The EMBO Journal 2024 study reports multiple statistically significant effects of UBAC2 perturbation/mutants on ER-phagy and inflammation-linked phenotypes, including comparisons with p < 0.0001 in several assays; in vivo DSS colitis experiments used n = 6 mice/group. (he2024erphagyrestrainsinflammatory pages 15-16, he2024erphagyrestrainsinflammatory pages 7-8)

Evidence map (key sources)

Year	Citation (first author journal)	URL	Evidence type (primary/review/database)	Key findings relevant to UBAC2 (function/pathway/localization/domains)	Key quantitative/statistical data (p-values, ORs, n)	Notes/limitations
2024	He, EMBO Journal	https://doi.org/10.1038/s44318-024-00232-z	Primary	Identifies human UBAC2 as an ER-resident ER-phagy receptor. UBAC2 contains a cytoplasmic canonical LIR that binds GABARAP; MARK2 phosphorylates UBAC2 at S223, promoting dimerization and stronger GABARAP binding. UBAC2-mediated ER-phagy restrains UPR/inflammatory signaling and protects against DSS colitis. UBAC2 also undergoes autophagic turnover during ER stress/starvation. (he2024erphagyrestrainsinflammatory pages 1-2, he2024erphagyrestrainsinflammatory pages 12-13, he2024erphagyrestrainsinflammatory pages 15-16, he2024erphagyrestrainsinflammatory pages 7-8, he2024erphagyrestrainsinflammatory pages 14-15, he2024erphagyrestrainsinflammatory pages 3-4)	HeLa ER-phagy reporter quantified across 3 biological replicates; 20 cells scored/condition in microscopy analyses; DSS colitis experiments used n=6 mice/group; multiple comparisons reported including p<0.0001, p=0.0100, p=0.0071, p=0.0012, p=0.0080. (he2024erphagyrestrainsinflammatory pages 12-13, he2024erphagyrestrainsinflammatory pages 15-16, he2024erphagyrestrainsinflammatory pages 7-8, he2024erphagyrestrainsinflammatory pages 3-4)	Strongest recent mechanistic study; extends UBAC2 function beyond ERAD into selective autophagy. Context excerpts do not provide all effect sizes/fold changes.
2019	Choi, Science	https://doi.org/10.1126/science.aau0812	Primary	Places UBAC2 in an ER-localized LMBR1L-GP78-UBAC2 complex that promotes ubiquitin-mediated degradation of FZD6/LRP6 and helps limit Wnt/β-catenin signaling in lymphocytes. Supports ER quality-control/ERAD-like function and ER localization. (choi2019lmbr1lregulateslymphopoiesis pages 1-2)	Paper reports impaired lymphoid development/function in mutant mice and restoration experiments involving β-catenin knockout, but quantitative values were not present in the available excerpt. (choi2019lmbr1lregulateslymphopoiesis pages 1-2)	Direct primary evidence for pathway-specific UBAC2 function, but excerpt does not state membrane topology or UBA-domain position.
2023	Bhaduri, Cold Spring Harbor Perspectives in Biology	https://doi.org/10.1101/cshperspect.a041248	Review	Reviews rhomboid superfamily roles in ER protein quality control and includes UBAC2 among rhomboid-like proteins linked to ERAD/proteostasis. Helps place UBAC2 in current ER quality-control framework. (OpenTargets Search: -UBAC2)	No UBAC2-specific quantitative statistics in available excerpt.	High-authority recent review; useful for current conceptual understanding, but mostly secondary synthesis rather than direct UBAC2 experiments.
2020	Adrain, FEBS Journal	https://doi.org/10.1111/febs.15548	Review	Describes UBAC2 as an ER-localized rhomboid pseudoprotease with a conserved C-terminal UBA domain; links UBAC2 to UBXD8, GP78-ERAD, delivery of substrates to GP78, and LMBR1L-GP78-UBAC2-mediated Wnt regulation. Notes Derlin-like behavior and unresolved physiology. (adrain2020thecomplexlife pages 15-18, adrain2020thecomplexlife pages 1-5)	No new quantitative UBAC2 statistics in excerpt.	Strong synthesis of mechanistic literature; some claims are review-level interpretations and precise physiological roles remain incompletely established.
2020	Kandel, BBA Mol Cell Res	https://doi.org/10.1016/j.bbamcr.2020.118793	Review	Summarizes UBAC2 as a rhomboid-like multi-pass membrane protein with a C-terminal UBA domain that binds polyubiquitin; UBAC2 knockdown stabilizes mutant α1-antitrypsin (an ERAD substrate) and UBAC2 restricts UBXD8 trafficking from ER to lipid droplets, linking proteostasis to lipid homeostasis. (kandel2020theroleof pages 10-14)	Quantitative values not included in excerpt; cites primary data that recombinant UBA binds polyubiquitin and knockdown stabilizes mutant α1-antitrypsin. (kandel2020theroleof pages 10-14)	Valuable for integrating ERAD and lipid-droplet biology; secondary source.
2016	Lemberg, Seminars in Cell & Developmental Biology	https://doi.org/10.1016/j.semcdb.2016.06.022	Review	Classifies UBAC2 as a rhomboid-family pseudoprotease predicted to bind ubiquitin via a conserved cytoplasmic C-terminal UBA domain; places it in the ERAD network with gp78 and identifies UBAC2 as an ER tether for UBXD8, affecting lipid-droplet trafficking and triglyceride turnover. (lemberg2016inactiverhomboidproteins pages 16-21)	No quantitative UBAC2-specific statistics in excerpt.	Foundational review; older and predates ER-phagy findings.
2013	Olzmann, Cold Spring Harbor Perspectives in Biology	https://doi.org/10.1101/cshperspect.a013185	Review	Early authoritative ERAD review explicitly mentions UBAC2 as a recently identified UBA-domain-containing, rhomboid-like factor in mammalian ERAD, helping establish the historical basis for UBAC2’s ER quality-control annotation. (OpenTargets Search: -UBAC2)	No UBAC2-specific quantitative data in available excerpt.	Important historical context, but limited UBAC2 detail in excerpt.
2012	Hou, Arthritis Research & Therapy	https://doi.org/10.1186/ar3789	Primary genetics/functional	Validates UBAC2 as a Behçet’s disease susceptibility locus in Han Chinese. Promoter SNP rs3825427 risk T allele reduces promoter activity and lowers UBAC2 transcript variant 1 in PBMCs/skin; variant 1 is decreased in BD, while variant 2 is increased in BD skin. (hou2012replicationstudyconfirms pages 4-5, hou2012replicationstudyconfirms pages 5-6, hou2012replicationstudyconfirms pages 1-2, hou2012replicationstudyconfirms pages 2-4, hou2012replicationstudyconfirms pages 6-7)	Two-stage study totaling 477 BD patients and 1,334 controls; rs9513584 Pc=0.018, OR=1.4; rs3825427 combined Pc=6.9×10^-6, OR=1.5; rs9517668 combined Pc=3.3×10^-4, OR=1.4; rs9517701 combined Pc=2.9×10^-5, OR=1.4; rs3825427 promoter assay P=0.002; transcript variant 1 genotype-expression P=0.045 and P=0.025; BD vs control expression P=0.025 and P=0.047; variant 2 in BD skin P=0.004. (hou2012replicationstudyconfirms pages 4-5, hou2012replicationstudyconfirms pages 5-6, hou2012replicationstudyconfirms pages 1-2, hou2012replicationstudyconfirms pages 2-4)	Strong disease-association and functional-regulatory evidence, but does not define biochemical mechanism of UBAC2 protein action.
2011	Nan, Human Molecular Genetics	https://doi.org/10.1093/hmg/ddr287	Primary genetics	GWAS implicates the UBAC2/PHGDHL1 region in skin cancer susceptibility, supporting medical relevance of the locus. (nan2011genomewideassociationstudy pages 1-2)	Discovery 2,045 BCC cases/6,013 controls; replication 1,426 cases/4,845 controls. rs7335046 near UBAC2: BCC OR 1.26 (95% CI 1.18–1.34), P=2.9×10^-8; SCC OR 1.21 (95% CI 1.02–1.44), P=0.03; rs12210050[T] SCC OR 1.35 (95% CI 1.16–1.57), P=7.6×10^-5. (nan2011genomewideassociationstudy pages 1-2)	Locus-level association only; does not establish UBAC2 as the causal effector gene or define function.
Current	Open Targets Platform	https://platform.opentargets.org/target/ENSG00000134882	Database	Aggregates disease-target associations for UBAC2, including asthma, childhood-onset asthma, psoriasis, actinic keratosis, and hypothyroidism, useful for prioritizing translational hypotheses. (OpenTargets Search: -UBAC2)	Example association scores from excerpt: asthma 0.4426; hypothyroidism 0.3475; actinic keratosis 0.3268; psoriasis 0.3055; childhood-onset asthma 0.3054; 5 literature-linked evidences per listed disease. (OpenTargets Search: -UBAC2)	Useful overview, but database evidence is heterogeneous and should not be treated as proof of causality without examining underlying studies.

Table: This table summarizes the main evidence base for human UBAC2 (Q8NBM4), highlighting the 2024 ER-phagy discovery paper, the 2019 Wnt/ERAD study, key reviews, and disease-genetics sources. It is useful for quickly separating direct mechanistic evidence from review synthesis and locus-level association data.

Conclusion

The best-supported “primary function” assignment for human UBAC2 has shifted from being primarily an ERAD-associated adapter in ubiquitin-dependent quality control to a broader role as a regulated ER-phagy receptor that connects ER stress to selective autophagy and inflammatory restraint. Mechanistically, the 2024 EMBO Journal work defines actionable molecular features (LIR–GABARAP binding, MARK2 phosphorylation at S223, dimerization) and demonstrates in vivo relevance in a colitis model, while earlier work supports UBAC2’s role in ER-localized ubiquitin-mediated degradation impacting Wnt signaling and immune development. (he2024erphagyrestrainsinflammatory pages 1-2, he2024erphagyrestrainsinflammatory pages 12-13, he2024erphagyrestrainsinflammatory pages 15-16, choi2019lmbr1lregulateslymphopoiesis pages 1-2)

URLs and publication dates (selected)

He et al., The EMBO Journal — Sep 2024 — https://doi.org/10.1038/s44318-024-00232-z (he2024erphagyrestrainsinflammatory pages 1-2)
Choi et al., Science — May 2019 — https://doi.org/10.1126/science.aau0812 (choi2019lmbr1lregulateslymphopoiesis pages 1-2)
Bhaduri et al., Cold Spring Harbor Perspectives in Biology — Aug 2023 — https://doi.org/10.1101/cshperspect.a041248 (OpenTargets Search: -UBAC2)
Hou et al., Arthritis Research & Therapy — Mar 2012 — https://doi.org/10.1186/ar3789 (hou2012replicationstudyconfirms pages 1-2)
Nan et al., Human Molecular Genetics — Jun 2011 — https://doi.org/10.1093/hmg/ddr287 (nan2011genomewideassociationstudy pages 1-2)
Open Targets: UBAC2 (ENSG00000134882) — https://platform.opentargets.org/target/ENSG00000134882 (OpenTargets Search: -UBAC2)

References

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Artifacts

Edison artifact artifact-00

Citations

he2024erphagyrestrainsinflammatory pages 7-8
he2024erphagyrestrainsinflammatory pages 12-13
he2024erphagyrestrainsinflammatory pages 15-16
nan2011genomewideassociationstudy pages 1-2
hou2012replicationstudyconfirms pages 4-5
kandel2020theroleof pages 10-14
lemberg2016inactiverhomboidproteins pages 16-21
he2024erphagyrestrainsinflammatory pages 1-2
hou2012replicationstudyconfirms pages 1-2
adrain2020thecomplexlife pages 15-18
adrain2020thecomplexlife pages 1-5
he2024erphagyrestrainsinflammatory pages 3-4
hou2012replicationstudyconfirms pages 5-6
he2024erphagyrestrainsinflammatory pages 14-15
hou2012replicationstudyconfirms pages 2-4
hou2012replicationstudyconfirms pages 6-7
T
https://doi.org/10.1038/s44318-024-00232-z
https://doi.org/10.1126/science.aau0812
https://doi.org/10.1101/cshperspect.a041248
https://doi.org/10.1111/febs.15548
https://doi.org/10.1016/j.bbamcr.2020.118793
https://doi.org/10.1016/j.semcdb.2016.06.022
https://doi.org/10.1101/cshperspect.a013185
https://doi.org/10.1186/ar3789
https://doi.org/10.1093/hmg/ddr287
https://platform.opentargets.org/target/ENSG00000134882
https://doi.org/10.1111/febs.15548,
https://doi.org/10.1016/j.bbamcr.2020.118793,
https://doi.org/10.1016/j.semcdb.2016.06.022,
https://doi.org/10.1126/science.aau0812,
https://doi.org/10.1038/s44318-024-00232-z,
https://doi.org/10.1093/hmg/ddr287,
https://doi.org/10.1186/ar3789,

OpenScientist

(UBAC2-hypotheses/function-hypothesis-go-0004252/openscientist.md)

UBAC2 Serine-Type Endopeptidase Activity Hypothesis: Final Report OpenScientist openscientist-autonomous 14 citations 26 artifacts 2026-07-04T22:42:44.624375 citations file

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UBAC2 Serine-Type Endopeptidase Activity Hypothesis: Final Report

Executive Judgment

Verdict: REFUTED — UBAC2 does not have serine-type endopeptidase activity (GO:0004252). The annotation should be removed.

UBAC2 (Q8NBM4) is a catalytically inactive member of the rhomboid-like superfamily — a rhomboid pseudoprotease. Five independent and convergent lines of evidence demonstrate that UBAC2 cannot function as a serine-type endopeptidase: (1) it lacks the GxSG catalytic serine motif in any transmembrane segment; (2) it possesses only 3 transmembrane helices versus the 6–7 required for active rhomboid protease architecture, entirely missing TM4–TM7 where both catalytic residues reside; (3) it has no catalytic histidine in any transmembrane context; (4) authoritative databases (InterPro IPR061914) and the very reference cited in the GO annotation (PMID:23297223) explicitly classify UBAC2 as a pseudoprotease; and (5) cross-species conservation analysis of 25 vertebrate orthologs confirms the catalytic residue loss is ancestral, predating the common ancestor of all sequenced vertebrates. No biochemical study has ever demonstrated protease activity for UBAC2.

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. This represents a systematic over-annotation problem affecting at least one other rhomboid pseudoprotease (iRhom2/RHBDF2). The annotation should be removed, and UBAC2's true molecular function — as an ER-resident pseudoprotease involved in ERAD and ER-phagy — should be reflected instead.

Summary

This investigation evaluated whether human UBAC2 (UniProt Q8NBM4) possesses serine-type endopeptidase activity (GO:0004252), as annotated by the PANTHER phylogenetic inference system (IBA evidence, GO_REF:0000033). Through three iterations of computational analysis, sequence comparison, structural topology assessment, and literature review, we conclusively determined that this annotation is incorrect.

UBAC2 belongs to the rhomboid-like superfamily but is a catalytically dead member — a pseudoprotease. Active rhomboid intramembrane proteases require a conserved GxSG motif housing the catalytic serine in transmembrane helix 4 (TM4) and a catalytic histidine in TM6, within a 6–7 TM architecture. UBAC2 has only 3 TM segments and completely lacks TM4–TM7, the structural half of the rhomboid fold that contains both catalytic residues. While UBAC2 contains a GxSG-like sequence (GSSG at positions 6–9), this motif resides in the N-terminal signal region, not in any transmembrane helix. All four histidine residues in UBAC2 are located outside transmembrane segments. This catalytic residue loss is not a recent evolutionary event: analysis of 25 UBAC2 orthologs spanning mammals, birds, and fish confirms that no vertebrate UBAC2 ortholog possesses catalytic residues, establishing that the loss predates the vertebrate common ancestor.

The primary literature is unambiguous. The very reference cited in the GO annotation — Olzmann et al. 2013 (PMID: 23297223) — refers to UBAC2 as "the ER-resident rhomboid pseudoprotease UBAC2." Subsequent studies have identified UBAC2's actual biological roles: it functions as an ER-phagy receptor (PMID: 39284914), participates in ERAD-related protein quality control, regulates lipid droplet biology via interaction with UBXD8, and modulates inflammatory signaling through the NF-κB pathway. None of these functions involve proteolytic activity.

Key Findings

Finding 1: UBAC2 Lacks the Catalytic Machinery for Serine Endopeptidase Activity

Active rhomboid intramembrane serine proteases employ a catalytic dyad consisting of a serine residue (within a conserved GxSG motif in TM4) and a histidine residue (in TM6). UBAC2 lacks both elements in any functionally relevant context. Sequence analysis of the full-length human UBAC2 protein (Q8NBM4, 344 residues) identified only one GxSG-like motif: GSSG at positions 6–9, located in the N-terminal signal/lumenal region, far from any transmembrane helix. No GxSG motif exists within the three transmembrane segments of UBAC2 (TM1: 92–112, TM2: 126–146, TM3: 164–184). The four histidine residues in UBAC2 (His36, His46 in the lumenal domain; His201, His344 in the cytoplasmic domain) are all outside transmembrane helices and cannot serve as catalytic partners.

InterPro entry IPR061914 explicitly classifies UBAC2 as a pseudoprotease: "These proteins are classified as pseudoproteases, as they are inactive members of the rhomboid-family." This classification is based on the systematic absence of catalytic residues, not merely on sequence divergence.

{{figure:ubac2_domain_comparison.png|caption=Domain architecture comparison between active rhomboid protease RHBDL2 (7 TM segments with catalytic Ser and His) and pseudoprotease UBAC2 (3 TM segments, no catalytic residues). UBAC2 is entirely missing the structural half (TM4–TM7) that houses both catalytic residues in active rhomboids.}}

Finding 2: UBAC2 Is Missing TM4–TM7 Where Both Catalytic Residues Reside

A detailed structural topology comparison between UBAC2 and the active rhomboid protease RHBDL2 revealed a fundamental architectural difference. RHBDL2 contains 7 transmembrane segments, with the catalytic serine in TM4 (Ser187 within the GASG motif) and the catalytic histidine in TM6 (His250). UBAC2 possesses only 3 TM segments. After TM3 (ending around position 184), the UBAC2 chain exits the membrane into a long cytoplasmic tail (positions 185–303) that contains the LC3-interacting region (LIR motif, positions 275–278), followed by the UBA (ubiquitin-associated) domain (positions 304–344).

This is not a subtle mutation of catalytic residues — it is the complete absence of the entire catalytic half of the rhomboid fold. Kyte-Doolittle hydropathy profiling confirmed this dramatic difference: RHBDL2 shows 7 distinct hydrophobic peaks corresponding to its 7 TM segments, while UBAC2 shows only 3, with the remainder of the protein being hydrophilic and cytoplasmic. AlphaFold structure confidence (pLDDT) analysis corroborated the topology, showing high confidence for the TM regions and decreasing confidence in the extended cytoplasmic tail.

{{figure:ubac2_vs_rhbdl2_hydropathy.png|caption=Kyte-Doolittle hydropathy profiles comparing active rhomboid RHBDL2 (7 TM segments, catalytic dyad marked) versus pseudoprotease UBAC2 (3 TM segments, no catalytic residues). The dramatic difference in membrane topology demonstrates that UBAC2 lacks the structural scaffold required for intramembrane proteolysis.}}

Finding 3: IBA Over-Annotation Affects Multiple Rhomboid Pseudoproteases

Investigation of the PANTHER phylogenetic tree revealed that the incorrect IBA annotation is not unique to UBAC2. At least one other known rhomboid pseudoprotease — iRhom2/RHBDF2 (Q6PJF5) — also carries the IBA GO:0004252 annotation. Other pseudoproteases in the family (RHBDF1, DERL1–3, TMEM115) do not, suggesting that PANTHER tree topology places UBAC2 and RHBDF2 closer to active rhomboid proteases like RHBDL1, causing inappropriate IBA propagation. Only bona fide active rhomboid proteases (RHBDL1–4 in mammals) should carry the serine-type endopeptidase annotation.

This finding highlights a systematic problem with automated phylogenetic annotation transfer in protein families that contain both active enzymes and catalytically inactive pseudoenzymes — a well-recognized challenge in the rhomboid superfamily (PMID: 27378062).

Finding 4: Catalytic Residue Loss Is Ancestral Across All Vertebrates

To determine whether the catalytic deficiency might be specific to human UBAC2 (or a recent loss event), we analyzed 25 UBAC2 orthologs from UniProt spanning the vertebrate tree: mammals (human, mouse, rat, cow, gorilla, bat, whale, dog, deer mouse), birds (chicken, finch, goose), and fish (tilapia). The result was unequivocal: 0 of 25 species have a GxSG catalytic motif in the TM region. Where GxSG occurs at all (12 of 25 species), it is exclusively at position 6–9 in the N-terminal signal region (as GSSG), never in any transmembrane helix. Chicken and fish orthologs lack even this N-terminal GxSG occurrence.

This confirms that the catalytic residue loss predates the common ancestor of all sequenced vertebrates — UBAC2 has never been a protease during vertebrate evolution. The conservation of the 3-TM architecture with cytoplasmic UBA domain across all vertebrates further indicates that UBAC2 was selected for a non-proteolytic function throughout its evolutionary history.

{{figure:ubac2_ortholog_conservation.png|caption=Cross-species conservation analysis of UBAC2 orthologs across 25 vertebrate species showing universal absence of catalytic residues in TM regions. The GxSG motif, when present, occurs only in the N-terminal signal region — never in a transmembrane helix.}}

Finding 5: Primary Literature Explicitly Identifies UBAC2 as a Pseudoprotease

Three independent authoritative sources classify UBAC2 as a pseudoprotease:

Olzmann et al. 2013 (PMID: 23297223) — the reference cited in the GO annotation itself — states: "association of UBXD8 with the ER-resident rhomboid pseudoprotease UBAC2 specifically restricts trafficking of UBXD8 to LDs." This is the single most important piece of evidence: the paper used to justify the annotation directly contradicts it.
InterPro IPR061914 classifies the UBAC2 family as pseudoproteases: "These proteins are classified as pseudoproteases, as they are inactive members of the rhomboid-family."
Bergbold & Lemberg 2013 (PMID: 23562403) reviews all 14 mammalian rhomboid family members, explicitly distinguishing "intramembrane serine proteases and diverse proteolytically inactive homologues" including "rhomboid pseudoproteases including iRhoms and derlins."

Additional reviews confirm the broader context. Lemberg & Adrain 2019 (PMID: 30890028) characterize iRhom proteins as "catalytically inactive relatives of rhomboid intramembrane proteases" that have "evolved new domains from their proteolytic ancestors." Zettl et al. 2011 (PMID: 21439629) established that "iRhoms are a conserved subfamily of proteins related to rhomboid intramembrane serine proteases that lack key catalytic residues."

Evidence Matrix

Citation	Evidence Type	Direction	Claim Tested	Key Finding	Context	Confidence
PMID: 23297223	Primary research	Refutes GO:0004252	UBAC2 protease activity	Calls UBAC2 "ER-resident rhomboid pseudoprotease" — the very reference in the annotation	Human, HeLa cells, lipid droplets	High — direct statement in cited reference
PMID: 39284914	Primary research	Refutes (competing function)	UBAC2 function	Identifies UBAC2 as an ER-phagy receptor, not a protease	Human, ER-phagy	High — most recent functional characterization
PMID: 23562403	Review	Refutes	Rhomboid family classification	Distinguishes active rhomboid proteases from inactive pseudoproteases	Mammalian rhomboid family (14 members)	High — comprehensive family review
PMID: 27378062	Review	Refutes	Pseudoprotease concept	Documents conserved catalytically inactive rhomboid homologs including derlins and iRhoms	Eukaryotic genomes	High — establishes pseudoprotease concept
PMID: 21439629	Primary research	Refutes	Catalytic residue requirements	iRhoms lack essential catalytic residues; use ER quality control instead of proteolysis	Drosophila, human	High — establishes catalytic residue criterion
PMID: 30890028	Review	Refutes	iRhom pseudoprotease function	iRhom proteins are catalytically inactive; regulate membrane protein trafficking	Metazoan	High — comprehensive mechanistic review
PMID: 34074311	Primary research	Competing function	UBAC2/TM4 biological role	UBAC2 (called TM4) regulates metabolic inflammation via Nur77/IKKβ/NF-κB; no protease activity described	Mouse KO, human visceral fat, Chinese Han population	Medium — functional but not catalytic activity study
PMID: 34618061	Primary research	Competing function	UBAC2 in plants	Arabidopsis UBAC2 homologs regulate COPT transporter accumulation; stabilize proteins against proteasomal degradation	Arabidopsis thaliana	Medium — plant ortholog; non-proteolytic function
InterPro IPR061914	Database/computational	Refutes	UBAC2 family classification	Explicitly classifies UBAC2 family as pseudoproteases: "inactive members of the rhomboid-family"	All UBAC2 orthologs	High — curated database classification
Computational: sequence analysis	Computational	Refutes	Catalytic motif presence	No GxSG in any TM; only 3 TM segments; no catalytic His in TM context	Human UBAC2 (Q8NBM4)	High — directly verifiable
Computational: ortholog analysis	Computational	Refutes	Species-specific loss	0/25 vertebrate orthologs have catalytic residues in TM; loss is ancestral	25 species: mammals, birds, fish	High — comprehensive sampling
Computational: hydropathy profile	Computational	Refutes	Membrane topology	Only 3 hydrophobic peaks (TM segments) vs 7 in active RHBDL2	Human UBAC2 vs RHBDL2	High — standard topology prediction

GO Curation Implications

Recommended Action: REMOVE GO:0004252 from UBAC2

The IBA annotation of serine-type endopeptidase activity (GO:0004252) for UBAC2 should be removed. This is not a borderline case requiring weakening or generalization — the annotation is fundamentally incorrect. UBAC2 is a pseudoprotease that has never possessed proteolytic activity during vertebrate evolution.

Specific recommendations:

Current Annotation	Action	Rationale
MF: GO:0004252 (serine-type endopeptidase activity), IBA	REMOVE	UBAC2 is a pseudoprotease; lacks catalytic residues and TM architecture; reference itself says "pseudoprotease"
—	Consider adding: GO:0005515 (protein binding) → more specific term	UBAC2 binds UBXD8, LC3, ubiquitin/NEDD8
—	Consider adding: GO:0140318 (cargo receptor activity for ER-phagy)	Recent evidence (PMID:39284914) identifies UBAC2 as ER-phagy receptor
—	Consider adding: GO:0030176 (integral component of ER membrane)	Well-established ER membrane localization
—	Consider adding: GO:0036503 (ERAD pathway) as BP	Functional role in ER-associated degradation

PANTHER tree correction needed: The PANTHER phylogenetic tree that generated this IBA annotation should be reviewed. The tree topology incorrectly groups UBAC2 with active rhomboid proteases. A similar correction may be needed for iRhom2/RHBDF2 (Q6PJF5), which also carries an incorrect IBA GO:0004252 annotation.

NOT-qualified annotation consideration: Given that UBAC2 is explicitly a pseudoprotease — evolutionarily derived from proteases but lacking activity — a curator might consider a NOT-qualified annotation (GO:0004252 with NOT qualifier) to explicitly document the absence, preventing re-annotation by future automated pipelines.

{{figure:ubac2_go_decision_table.png|caption=GO curation decision table summarizing the recommended annotation changes for UBAC2, including removal of the incorrect serine endopeptidase annotation and candidate replacement terms reflecting UBAC2's actual biological functions.}}

Mechanistic Scope

Direct Molecular Function of UBAC2

UBAC2 is an ER-resident integral membrane pseudoprotease with the following established molecular functions:

ER-phagy receptor: UBAC2 was recently identified as a receptor for selective autophagy of ER membranes (ER-phagy) (PMID: 39284914). It contains a functional LIR (LC3-interacting region) motif at positions 275–278 in the cytoplasmic tail and a UBA (ubiquitin-associated) domain at positions 304–344.
UBXD8 trafficking regulator: UBAC2 interacts with UBXD8 in the ER membrane and restricts UBXD8 trafficking to lipid droplets (PMID: 23297223).
Metabolic inflammation modulator: As "TM4," UBAC2 counterregulates the Nur77/IKKβ/NF-κB signaling axis, and UBAC2 knockout mice develop obesity, hepatosteatosis, hypertension, and glucose intolerance on a high-fat diet (PMID: 34074311).
Protein stabilization (in plants): Arabidopsis UBAC2 homologs stabilize newly synthesized COPT copper transporters against proteasomal degradation (PMID: 34618061).

Separation from Downstream Phenotypes

The GWAS associations of UBAC2 polymorphisms with Behçet's disease (PMID: 30069262; PMID: 28389674), noise-induced hearing loss (PMID: 35020141), bladder cancer (PMID: 32913183), and uveitis (PMID: 26310161) are downstream disease associations that do not inform the molecular function assignment. Importantly, the UBAC2 locus overlaps with GPR183 on the reverse strand (PMID: 33145756), complicating genetic attribution. None of these disease associations involve or imply proteolytic activity.

Conflicts and Alternatives

The Core Conflict: Family Membership vs. Catalytic Competence

The sole basis for the GO:0004252 annotation is phylogenetic inference (IBA from PANTHER). UBAC2 is a member of the rhomboid-like superfamily, and PANTHER's tree topology placed it close enough to active rhomboid proteases to trigger annotation transfer. However, the rhomboid superfamily is well-established to contain both active proteases and catalytically dead pseudoproteases (PMID: 27378062; PMID: 23562403). Family membership alone is insufficient evidence for catalytic activity in a superfamily with known pseudoenzymes.

No Competing Evidence Supports Protease Activity

Despite extensive literature search (20 papers reviewed across 3 iterations), no study has ever reported protease activity for UBAC2. No substrate cleavage, no protease assay, no active-site labeling — the evidence for protease activity is entirely absent. All functional studies describe non-proteolytic roles (protein trafficking, autophagy receptor, inflammatory signaling).

Alternative Interpretation: Regulatory Pseudoenzyme

The most parsimonious interpretation is that UBAC2, like other rhomboid pseudoproteases (iRhoms, derlins), has been repurposed during evolution from a protease ancestor into a regulatory protein that uses its remaining membrane-embedded domain for protein-protein interactions rather than catalysis. This is consistent with the broader "pseudoenzyme" concept now well-recognized across enzyme superfamilies.

Potential Confounders

Locus overlap: UBAC2 shares a genomic locus with GPR183 (on the reverse strand), which encodes the oxysterol receptor involved in immune cell trafficking. Some disease associations attributed to UBAC2 may actually reflect GPR183 variation.
Naming confusion: Some literature refers to UBAC2 as "TM4" (PMID: 34074311), which could cause confusion with transmembrane domain 4 of other proteins.

Knowledge Gaps

Gap	What Was Checked	Why It Matters	What Would Resolve It
No direct protease assay on recombinant UBAC2	Literature search found no biochemical protease assays	Absence of evidence is not evidence of absence (though strongly suggestive given structural data)	In vitro protease assay with purified UBAC2 and model substrates (e.g., fluorogenic peptides or transmembrane substrates)
PANTHER tree topology details	Identified the over-annotation but could not access the full PANTHER tree	Understanding the exact branching error would help prevent similar over-annotations	Review of PANTHER family PTHR13691 or equivalent tree containing rhomboid proteins
Structural comparison to active rhomboid at atomic level	AlphaFold model analyzed for pLDDT and TM topology	A structural superposition would definitively show the absence of the catalytic site geometry	Superpose UBAC2 AlphaFold model onto GlpG crystal structure (PDB: 2IC8) at the active site region
Ancestral reconstruction of catalytic residue loss	Sampled 25 vertebrate orthologs; all lack catalytic residues	Pinpointing when the loss occurred in evolution would strengthen the pseudoprotease classification	Extended analysis including invertebrate orthologs and phylogenetic reconstruction of the catalytic dyad loss
Full spectrum of rhomboid pseudoprotease IBA annotations	Checked UBAC2 and RHBDF2; both have incorrect IBA	Systematic correction needed across the family	Comprehensive audit of all IBA GO:0004252 annotations in the rhomboid superfamily

Discriminating Tests

Definitive Experiments

In vitro protease assay: Express and purify full-length UBAC2 in a membrane-mimetic system (nanodiscs or liposomes). Test for cleavage of known rhomboid substrates (e.g., Spitz, EGF-family ligands, model TM substrates with fluorogenic reporters). Expected result: No cleavage activity, confirming pseudoprotease status.
Active-site labeling with fluorophosphonate probes: Use activity-based probes (e.g., FP-rhodamine) that react specifically with active serine hydrolases. Compare UBAC2 to active RHBDL2. Expected result: No labeling of UBAC2.
Catalytic residue restoration mutagenesis: Engineer a UBAC2 construct with TM4–TM7 from RHBDL2 grafted in, including the GxSG and catalytic His. Test for gain of protease activity. Expected result: Chimera might gain partial activity, definitively proving UBAC2's own sequence lacks it.

Computational Analyses

PANTHER tree audit: Systematically identify all rhomboid superfamily members carrying IBA GO:0004252 and cross-reference against catalytic residue presence/absence.
Structural superposition: Superpose UBAC2 AlphaFold model (AF-Q8NBM4-F1) onto the crystal structure of E. coli GlpG rhomboid protease (PDB: 2IC8) to visualize the absent catalytic geometry at atomic resolution.

Curation Leads

Lead 1: Remove GO:0004252 (serine-type endopeptidase activity) — HIGH PRIORITY

Action: Remove the IBA annotation of GO:0004252 from UBAC2 (Q8NBM4)
Rationale: Pseudoprotease lacking all catalytic requirements; reference itself contradicts the annotation
Key reference to verify: PMID: 23297223 — exact snippet: "association of UBXD8 with the ER-resident rhomboid pseudoprotease UBAC2 specifically restricts trafficking of UBXD8 to LDs"
Confidence: Very high — multiple independent evidence lines converge

Lead 2: Consider NOT-Qualified Annotation

Action: Add GO:0004252 with NOT qualifier to prevent re-annotation
Rationale: UBAC2 is evolutionarily derived from serine proteases but explicitly lacks the activity; a NOT annotation would document this and prevent future automated re-annotation
Suggested evidence code: IDA (if protease assay is performed) or ISS (based on structural analysis showing absence of catalytic residues)

Lead 3: Add Candidate Positive Annotations

GO:0140318 (cargo receptor activity) or parent term — based on PMID: 39284914
Snippet to verify: "we identified ubiquitin-associated domain-containing protein 2 (UBAC2) as a receptor for ER-phagy"
GO:0030176 (integral component of ER membrane) — well-established localization
GO:0036503 (ERAD pathway) as BP annotation — established functional context

Lead 4: Flag RHBDF2/iRhom2 for Same Correction

Action: Check and likely remove GO:0004252 IBA annotation from RHBDF2 (Q6PJF5)
Rationale: iRhom2 is another established rhomboid pseudoprotease; same PANTHER tree error
Key reference: PMID: 30890028 — "iRhom proteins are catalytically inactive relatives of rhomboid intramembrane proteases"

Lead 5: Report PANTHER Tree Issue

Action: Flag PANTHER family tree for rhomboid superfamily for review
Rationale: Tree topology fails to distinguish active proteases from pseudoproteases, leading to systematic over-annotation
Suggested question for PANTHER team: Can the tree be refined to place rhomboid pseudoproteases (UBAC2, RHBDF1/2, DERL1–3) in a separate clade from active rhomboid proteases (RHBDL1–4)?

Evidence Base: Key Literature

Papers Directly Refuting the Hypothesis

Olzmann JA et al. (2013) Spatial regulation of UBXD8 and p97/VCP controls ATGL-mediated lipid droplet turnover. PMID: 23297223 — The reference cited in the GO annotation. Explicitly calls UBAC2 "the ER-resident rhomboid pseudoprotease UBAC2." This single paper is sufficient to refute the annotation, as the source reference contradicts the derived annotation.
Bergbold N & Lemberg MK (2013) Emerging role of rhomboid family proteins in mammalian biology and disease. PMID: 23562403 — Comprehensive review of all 14 mammalian rhomboid family members, distinguishing "intramembrane serine proteases and diverse proteolytically inactive homologues."
Düsterhöft S et al. (2017) Inactive rhomboid proteins: New mechanisms with implications in health and disease. PMID: 27378062 — Documents that "eukaryotic genomes harbor conserved catalytically inactive rhomboid protease homologs, including derlins and iRhoms."
Zettl M et al. (2011) Rhomboid family pseudoproteases use the ER quality control machinery to regulate intercellular signaling. PMID: 21439629 — Established that "iRhoms are a conserved subfamily of proteins related to rhomboid intramembrane serine proteases that lack key catalytic residues."

Papers Defining UBAC2's Actual Functions

He Q et al. (2024) ER-phagy restrains inflammatory responses through its receptor UBAC2. PMID: 39284914 — Most recent functional study identifying UBAC2 as an ER-phagy receptor, a non-proteolytic function.
Zhu P et al. (2021) PS-341 alleviates chronic low-grade inflammation and improves insulin sensitivity through the inhibition of TM4 (UBAC2) degradation. PMID: 34074311 — Characterizes UBAC2 (as "TM4") in metabolic inflammation via Nur77/IKKβ/NF-κB axis; no protease activity described.
Lemberg MK & Adrain C (2019) The molecular, cellular and pathophysiological roles of iRhom pseudoproteases. PMID: 30890028 — Comprehensive review of pseudoprotease function: "catalytically inactive relatives of rhomboid intramembrane proteases" that "regulate the stability and trafficking of other membrane proteins."

Disease Association Papers (Informative but Not Relevant to MF Annotation)

PMID: 28389674, PMID: 30069262, PMID: 35020141, PMID: 32913183, PMID: 33145756 — These papers associate UBAC2 polymorphisms with various diseases (Behçet's, hearing loss, bladder cancer, IBD) but do not inform the molecular function assignment. None describe or imply proteolytic activity.

Limitations

No negative experimental result exists: While the structural and sequence evidence is overwhelming, no published study has explicitly tested and failed to detect UBAC2 protease activity in a biochemical assay. The evidence is therefore structural/computational rather than direct experimental disproof.
AlphaFold model limitations: The structural topology analysis relied partly on the AlphaFold predicted structure, which may not capture all conformational states or post-translational modifications. However, the topology conclusions are independently confirmed by hydropathy profiling and UniProt topology annotations.
Ortholog sampling: While 25 vertebrate orthologs were analyzed, invertebrate orthologs were not systematically examined. The ancestral loss likely predates vertebrates, but the exact evolutionary timing remains uncertain.
Potential for non-canonical catalysis: While extremely unlikely, it is theoretically possible that UBAC2 could perform a non-canonical form of catalysis using a mechanism entirely different from the classical rhomboid serine protease mechanism. No evidence supports this possibility.

Proposed Follow-up Actions

Immediate Curation Actions

Remove GO:0004252 (serine-type endopeptidase activity) from UBAC2 — the evidence is conclusive
Add NOT GO:0004252 to prevent automated re-annotation
Flag RHBDF2 for the same correction
Report to PANTHER the need for tree refinement in the rhomboid superfamily

Recommended Experiments

Activity-based profiling: Test UBAC2 with serine hydrolase activity-based probes (FP-probes) alongside active RHBDL2 as positive control
In vitro cleavage assay: Reconstitute UBAC2 in proteoliposomes with fluorogenic TM substrates
ER-phagy receptor characterization: Further biochemical characterization of UBAC2's LIR motif and UBA domain interactions to support positive GO annotations

Computational Follow-ups

Full rhomboid superfamily IBA audit: Identify all proteins with IBA GO:0004252 and cross-check for pseudoprotease status
Structural superposition: UBAC2 AlphaFold model vs. GlpG crystal structure (PDB: 2IC8)
Invertebrate ortholog analysis: Extend conservation analysis to determine when the catalytic dyad was lost in the rhomboid pseudoprotease lineage

{{figure:ubac2_evidence_summary.png|caption=Comprehensive evidence summary comparing UBAC2 to active rhomboid proteases across all critical structural and catalytic features. Every line of evidence converges on the same conclusion: UBAC2 is a pseudoprotease lacking serine endopeptidase activity.}}

Artifacts

📚 Additional Documentation

Notes

(UBAC2-notes.md)

UBAC2 (UBA domain-containing protein 2) review notes

UniProt: Q8NBM4 (UBAC2_HUMAN), 344 aa precursor. Synonym PHGDHL1, PSEC0110. HGNC:20486.
Multi-pass ER-membrane protein with an N-terminal rhomboid-like (pseudoprotease) fold and a
C-terminal cytoplasmic UBA domain (304-344). It is a rhomboid-family pseudoprotease — the
catalytic Ser/His dyad of active rhomboid proteases is NOT conserved, so it has no protease activity.

Core biology

ERAD membrane component (RHBDD1/UBAC2 machinery). UBAC2 partners the active rhomboid protease
RHBDD1 in ER-associated degradation of membrane substrates; its cytoplasmic UBA domain binds
ubiquitinated substrates. (This RHBDD1/UBAC2 role is well established in the ERAD literature; note
the current GOA TSV does not contain a direct RHBDD1-co-annotation, so it is captured in the
description/core_functions rather than as an existing annotation review.)
FAF2/UBXD8 ER receptor. UBAC2 is the ER receptor that restricts trafficking of FAF2/UBXD8 from
the ER to lipid droplets.
PMID:23297223
This is the basis of the IDA ER localization and "protein localization to ER" annotations (MGI,
PMID:23297223), and the IMP "negative regulation of retrograde protein transport ER to cytosol"
(PMID:25660456).
ER-phagy receptor. UBAC2 is an ER-phagy (reticulophagy) receptor with a LIR motif that binds
GABARAP; MARK2 phosphorylates UBAC2 at Ser223 to drive dimerization and GABARAP binding, restraining
inflammatory responses.
PMID:39284914
Wnt regulation. With LMBR1L and the E3 ligase AMFR, UBAC2 negatively regulates canonical Wnt
signaling in lymphocytes by promoting degradation of CTNNB1 and Wnt receptors FZD6/LRP6.
PMID:31073040

Annotation assessment summary

serine-type endopeptidase activity (GO:0004252) IBA: UBAC2 is a rhomboid pseudoprotease lacking
the catalytic dyad; this IBA is an over-propagation from the active-rhomboid branch of the PANTHER tree
and is biologically incorrect → REMOVE (IEA/IBA over-propagation, refutable on biological grounds).
ER membrane (GO:0005789 IEA) / ER (GO:0005783 IDA): core compartment → ACCEPT.
protein localization to ER (GO:0070972) / negative regulation of retrograde protein transport ER to
cytosol (GO:1904153): reflect the FAF2/UBXD8 ER-receptor role → ACCEPT.
reticulophagy (GO:0061709) / negative regulation of inflammatory response (GO:0050728) IMP: ER-phagy
receptor role → ACCEPT.
negative regulation of canonical Wnt (GO:0090090) IMP/IEA: LMBR1L/AMFR Wnt role → ACCEPT (non-core
relative to ERAD/ER-phagy, but experimentally supported).
protein binding (GO:0005515) IPI: uninformative term → KEEP_AS_NON_CORE.

Falcon deep-research findings (incorporated 2026-06)

The Falcon report largely corroborates the existing review (ER-phagy receptor / MARK2 / Ser223 /
GABARAP, LMBR1L-AMFR Wnt regulation, FAF2/UBXD8 ER receptor, ERAD, rhomboid pseudoprotease). The
genuinely new, verifiable additions are the disease-genetics references:

UBAC2 is a confirmed Behçet's disease (BD) susceptibility locus in Han Chinese (two-stage study,
477 BD cases / 1,334 controls). The risk T allele of promoter SNP rs3825427 has lower promoter
activity and lowers UBAC2 transcript variant 1 expression, suggesting disease risk acts via
transcriptional modulation of UBAC2. PMID:22455605 (PubMed-verified; doi:10.1186/ar3789). Added as a top-level reference
(relevance MEDIUM) — locus/regulatory evidence, not tied to a specific GO term.
The 13q32 locus near UBAC2 (variant rs7335046) confers susceptibility to cutaneous basal cell
carcinoma and squamous cell carcinoma. PMID:21700618 (PubMed-verified; doi:10.1093/hmg/ddr287). Added as a top-level reference
(relevance LOW) — locus-level GWAS only, does not establish UBAC2 as the causal gene.
Falcon also cites several rhomboid/ERAD reviews (Adrain 2020 FEBS J doi:10.1111/febs.15548; Kandel
2020 BBA-MCR doi:10.1016/j.bbamcr.2020.118793; Lemberg 2016 Semin Cell Dev Biol
doi:10.1016/j.semcdb.2016.06.022) reiterating the UBA-domain/polyubiquitin-binding adapter and
FAF2/UBXD8 lipid-droplet-trafficking role already captured in the review; not added as separate
references since they only restate existing primary-evidence-backed content.
Note: the Falcon report repeatedly cites the ER-phagy paper as "doi:10.1038/s44318-024-00232-z";
this is the same study already in the review as PMID:39284914 (He et al. 2024, EMBO J). No new
ER-phagy finding beyond what is already annotated.

Pn Notes

(UBAC2-pn-notes.md)

UBAC2 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q8NBM4
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-11
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/UBAC2/UBAC2-ai-review.yaml
AIGR review HTML: missing - genes/human/UBAC2/UBAC2-ai-review.html
Gene notes: present - genes/human/UBAC2/UBAC2-notes.md
GOA TSV: present - genes/human/UBAC2/UBAC2-goa.tsv
UniProt record: present - genes/human/UBAC2/UBAC2-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/UBAC2.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/UBAC2.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

genes/human/UBAC2/UBAC2-deep-research-falcon.md

AIGR Review Snapshot

Description: UBAC2 (ubiquitin-associated domain-containing protein 2, also PHGDHL1) is a multi-pass endoplasmic reticulum (ER) membrane protein of the rhomboid superfamily. Its N-terminal region adopts a rhomboid-like fold but is a catalytically inactive pseudoprotease (it lacks the conserved serine-protease catalytic dyad), and its C-terminal cytoplasmic UBA domain binds ubiquitin. UBAC2 acts as an ER-membrane scaffolding/adaptor component rather than an enzyme. It partners the active rhomboid protease RHBDD1 in the ER-associated degradation (ERAD) of membrane substrates, where its UBA domain engages ubiquitinated clients. UBAC2 is also the ER receptor that binds FAF2/UBXD8 and restricts FAF2 trafficking from the ER to lipid droplets, thereby modulating ER-to-cytosol dislocation and lipid-droplet partitioning. Independently, UBAC2 serves as a selective autophagy (ER-phagy/reticulophagy) receptor; a LIR motif in its cytoplasmic domain binds the autophagosomal protein GABARAP, and MARK2-mediated phosphorylation at Ser223 promotes UBAC2 dimerization and GABARAP binding to drive ER-phagy, which in turn restrains ER-stress-induced inflammatory responses. In a complex with LMBR1L and the E3 ubiquitin ligase AMFR, UBAC2 also negatively regulates canonical Wnt/beta-catenin signaling in lymphocytes by promoting degradation of CTNNB1 and the Wnt receptors FZD6 and LRP6.
Existing/core annotation action counts: ACCEPT: 8; KEEP_AS_NON_CORE: 6; REMOVE: 1

PN Consistency Summary

Consistency: Excellent. Deep research, review and PN concur that UBAC2 is a catalytically inactive rhomboid pseudoprotease (no Ser/His dyad), an ER-membrane scaffold/adaptor — NOT an enzyme. The PN explicitly tags the LMBR1L-GP78-UBAC2 subtype as "noncatalytic / UBA, transmembrane" and assigns the COMPLEX (GO:0000151), not catalytic activity, to the group — exactly matching the review's REMOVE of the IBA serine-type endopeptidase activity (GO:0004252). The PN correctly does NOT project GO:0061630 to UBAC2. No contradictions.
PN story / NEW pressure: PN's only NEW projection is GO:0000151 ubiquitin ligase complex (verified real; NOT in GOA) from the LMBR1L-GP78(AMFR)-UBAC2 idiosyncratic-RING-complex membership (PMID:31073040). UBAC2 is genuinely a non-catalytic subunit of this AMFR/GP78-containing E3 complex, so complex membership is a DEFENSIBLE ADD — and one the review does NOT currently capture (review has the Wnt BP via this complex but no GO:0000151 CC term). Conclude: pseudoprotease/scaffold correctly captured; GO:0000151 a defensible NEW the review missed.
Evidence alignment: Partial. PN complex row cites "31073040" (LMBR1L/Wnt paper) — IS in the review (HIGH/VERIFIED, source of the Wnt + LMBR1L annotations). The ERphagy row carries no PN reference title; the review's ER-phagy evidence (PMID:39284914, HIGH) is gene-specific and richer. Good overlap on the one cited PMID; no divergence.
Verdict: Fully consistent; pseudoprotease status and scaffold role correctly handled by BOTH review (REMOVE GO:0004252) and PN (noncatalytic tag, no GO:0061630). GO:0000151 complex membership is a defensible ADD the review omits.

Full Consistency Review

UniProt: Q8NBM4 · batch: proteostasis-batch-2026-06-11 · review status: COMPLETE (thorough; rhomboid PSEUDOprotease, ERAD scaffold + FAF2 ER receptor + ER-phagy receptor + Wnt)
PN placement: 2 rows — UPS|E3 ubiquitin and UBL ligases|idiosyncratic RING complex|LMBR1L-GP78-UBAC2 complex|noncatalytic / UBA, transmembrane; UPS|Ubiquitin and UBL binding|trafficking|ERphagy|UBA. PN-node mapping: LMBR1L-GP78-UBAC2 subtype/type no_mapping (noncatalytic, covered by parent); idiosyncratic-RING-complex group→GO:0000151 ubiquitin ligase complex (new_to_goa); E3-ligase class context_only GO:0061630 (too_broad); ERphagy/UBA-binding rows all no_mapping/context_only (GO:0140036 too_broad). Projected: GO:0000151 (new).
Consistency: Excellent. Deep research, review and PN concur that UBAC2 is a catalytically inactive rhomboid pseudoprotease (no Ser/His dyad), an ER-membrane scaffold/adaptor — NOT an enzyme. The PN explicitly tags the LMBR1L-GP78-UBAC2 subtype as "noncatalytic / UBA, transmembrane" and assigns the COMPLEX (GO:0000151), not catalytic activity, to the group — exactly matching the review's REMOVE of the IBA serine-type endopeptidase activity (GO:0004252). The PN correctly does NOT project GO:0061630 to UBAC2. No contradictions.
PN story / NEW pressure: PN's only NEW projection is GO:0000151 ubiquitin ligase complex (verified real; NOT in GOA) from the LMBR1L-GP78(AMFR)-UBAC2 idiosyncratic-RING-complex membership (PMID:31073040). UBAC2 is genuinely a non-catalytic subunit of this AMFR/GP78-containing E3 complex, so complex membership is a DEFENSIBLE ADD — and one the review does NOT currently capture (review has the Wnt BP via this complex but no GO:0000151 CC term). Conclude: pseudoprotease/scaffold correctly captured; GO:0000151 a defensible NEW the review missed.
Mapping strategy: Exemplary. Resolves the pseudoprotease trap (no serine endopeptidase MF — matches prior REMOVE precedent), assigns complex membership not catalysis to the non-catalytic subunit, and conservatively leaves the ERphagy/UBA-binding rows unmapped (avoids over-broad GO:0140036 reader propagation). The ER-phagy biology IS captured at the gene level (review GO:0061709 reticulophagy IMP). No node-status change warranted.
Evidence alignment: Partial. PN complex row cites "31073040" (LMBR1L/Wnt paper) — IS in the review (HIGH/VERIFIED, source of the Wnt + LMBR1L annotations). The ERphagy row carries no PN reference title; the review's ER-phagy evidence (PMID:39284914, HIGH) is gene-specific and richer. Good overlap on the one cited PMID; no divergence.
Verdict: Fully consistent; pseudoprotease status and scaffold role correctly handled by BOTH review (REMOVE GO:0004252) and PN (noncatalytic tag, no GO:0061630). GO:0000151 complex membership is a defensible ADD the review omits.
Recommended edits: [YAML] add GO:0000151 ubiquitin ligase complex (part_of; LMBR1L-AMFR/GP78-UBAC2 complex, PMID:31073040) as a non-core CC — currently absent from the review. [MAP] none — node mapping is correct; complex (not catalytic) target for the non-catalytic subunit is the right call.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-11
review_yaml: genes/human/UBAC2/UBAC2-ai-review.yaml
PN workbook rows: 2

PN row 1: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | idiosyncratic RING complex | LMBR1L-GP78-UBAC2 complex | noncatalytic / UBA, transmembrane

UniProt: Q8NBM4
In branches: UPS
Signature domains: (none)
Auxiliary domains: IPR015940
PN references (titles):
- 31073040
PN-node mapping records (path + ancestors):
- [subtype] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|idiosyncratic RING complex|LMBR1L-GP78-UBAC2 complex|noncatalytic / UBA, transmembrane
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a narrower E3-ligase architecture, component, or domain subdivision already covered by the curated parent E3 mapping. No additional direct GO mapping is needed at this node.
- [type] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|idiosyncratic RING complex|LMBR1L-GP78-UBAC2 complex
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a narrower E3-ligase architecture, component, or domain subdivision already covered by the curated parent E3 mapping. No additional direct GO mapping is needed at this node.
- [group] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|idiosyncratic RING complex
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0000151 ubiquitin ligase complex]
  rationale: This PN group is an E3 ligase complex bucket. The safest shared GO target is ubiquitin ligase complex membership rather than assigning catalytic activity to every subunit.
- [class] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases
  status=context_only scope=too_broad_to_propagate GO=[GO:0061630 ubiquitin protein ligase activity]
  rationale: This class is a genuine E3-ligase context, but its descendants include catalytic ligases, cullin scaffolds, substrate receptors, adaptors, cofactors, regulators, and UBL modifier systems. A class-level propagation would over-annotate.
- [branch] Ubiquitin Proteasome System
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.

PN row 2: Ubiquitin Proteasome System | Ubiquitin and UBL binding | trafficking | ERphagy | UBA

UniProt: Q8NBM4
In branches: UPS
Signature domains: IPR015940
Auxiliary domains: (none)
PN-node mapping records (path + ancestors):
- [subtype] Ubiquitin Proteasome System|Ubiquitin and UBL binding|trafficking|ERphagy|UBA
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a selective-autophagy or trafficking subdivision under a UPS binding context. The autophagy context is real, but this node is too indirect for automatic GO propagation.
- [type] Ubiquitin Proteasome System|Ubiquitin and UBL binding|trafficking|ERphagy
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a UPS taxonomy container. Its descendants mix catalytic roles, complex membership, binding domains, regulators, adaptors, and substrate-context labels, so a single propagating GO assertion would overstate the shared biology.
- [group] Ubiquitin Proteasome System|Ubiquitin and UBL binding|trafficking
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a UPS taxonomy container. Its descendants mix catalytic roles, complex membership, binding domains, regulators, adaptors, and substrate-context labels, so a single propagating GO assertion would overstate the shared biology.
- [class] Ubiquitin Proteasome System|Ubiquitin and UBL binding
  status=context_only scope=too_broad_to_propagate GO=[GO:0140036 ubiquitin-modified protein reader activity]
  rationale: This class records ubiquitin/UBL-reader context, but the subtree mixes ubiquitin, SUMO, UBL-domain, domain-architecture, catalytic, signaling, trafficking, and nucleic-acid process buckets. It is useful context, not a safe direct propagation.
- [branch] Ubiquitin Proteasome System
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.

Projected GO annotations (1)

GO:0000151 ubiquitin ligase complex | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|idiosyncratic RING complex

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

id: Q8NBM4
gene_symbol: UBAC2
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  UBAC2 (ubiquitin-associated domain-containing protein 2, also PHGDHL1) is a
  multi-pass endoplasmic reticulum (ER) membrane protein of the rhomboid
  superfamily. Its N-terminal region adopts a rhomboid-like fold but is a
  catalytically inactive pseudoprotease (it lacks the conserved serine-protease
  catalytic dyad), and its C-terminal cytoplasmic UBA domain binds ubiquitin.
  UBAC2 acts as an ER-membrane scaffolding/adaptor component rather than an
  enzyme. It partners the active rhomboid protease RHBDD1 in the ER-associated
  degradation (ERAD) of membrane substrates, where its UBA domain engages
  ubiquitinated clients. UBAC2 is also the ER receptor that binds FAF2/UBXD8 and
  restricts FAF2 trafficking from the ER to lipid droplets, thereby modulating
  ER-to-cytosol dislocation and lipid-droplet partitioning. Independently, UBAC2
  serves as a selective autophagy (ER-phagy/reticulophagy) receptor; a LIR motif
  in its cytoplasmic domain binds the autophagosomal protein GABARAP, and
  MARK2-mediated phosphorylation at Ser223 promotes UBAC2 dimerization and
  GABARAP binding to drive ER-phagy, which in turn restrains ER-stress-induced
  inflammatory responses. In a complex with LMBR1L and the E3 ubiquitin ligase
  AMFR, UBAC2 also negatively regulates canonical Wnt/beta-catenin signaling in
  lymphocytes by promoting degradation of CTNNB1 and the Wnt receptors FZD6 and
  LRP6.
alternative_products:
- name: '1'
  id: Q8NBM4-1
- name: '2'
  id: Q8NBM4-2
  sequence_note: VSP_023911, VSP_023912
- name: '3'
  id: Q8NBM4-3
  sequence_note: VSP_023910
- name: '4'
  id: Q8NBM4-4
  sequence_note: VSP_023909
- name: '5'
  id: Q8NBM4-5
  sequence_note: VSP_023913, VSP_023914
existing_annotations:
- term:
    id: GO:0004252
    label: serine-type endopeptidase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: UBAC2 belongs to the rhomboid superfamily but is a catalytically inactive pseudoprotease; the UniProt record and ERAD literature describe it as a rhomboid pseudoprotease lacking the serine-protease catalytic dyad. This IBA is propagated from the active-rhomboid branch of the phylogenetic tree and is biologically incorrect for UBAC2.
    action: REMOVE
    reason: UBAC2 is a rhomboid pseudoprotease with no protease activity; the serine-type endopeptidase activity is an over-propagated phylogenetic inference refuted on biological grounds (no catalytic residues). OpenScientist independently refuted the activity assignment and traced it to transfer from active rhomboid proteases.
    propagation_review:
      root_cause: PROPAGATION_BAD
      failure_modes:
      - WRONG_ORTHOLOG_OR_PARALOG
      - PSEUDO_OR_SUBACTIVITY_LOSS
      source_entities:
      - source_id: GO_REF:0000033
        source_label: PAINT phylogenetic IBA inference
        source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET
        comment: The family-level inference transfers serine endopeptidase activity
          from active rhomboid proteases, but UBAC2 is a rhomboid pseudoprotease
          lacking the catalytic residues and topology needed for protease activity.
    supported_by:
    - reference_id: PMID:23297223
      supporting_text: the ER-resident rhomboid pseudoprotease UBAC2
    - reference_id: file:human/UBAC2/UBAC2-hypotheses/function-hypothesis-go-0004252/openscientist.md
      supporting_text: UBAC2 does not have serine-type endopeptidase activity (GO:0004252).
        The annotation should be removed.
    - reference_id: file:human/UBAC2/UBAC2-hypotheses/function-hypothesis-go-0004252/openscientist.md
      supporting_text: 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.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: UBAC2 is a multi-pass ER membrane protein; the electronic subcellular-location assignment is consistent with direct experimental evidence.
    action: ACCEPT
    reason: Core compartment; UBAC2 is an integral ER membrane protein.
    supported_by:
    - reference_id: file:human/UBAC2/UBAC2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22119785
  qualifier: enables
  review:
    summary: ERAD-network interactome capture of the UBAC2-FAF2 interaction. The bare protein binding term is uninformative; the functional relationship is captured by the FAF2/ER-receptor annotations.
    action: KEEP_AS_NON_CORE
    reason: Real ERAD-network interaction (FAF2) but uninformative GO term.
    supported_by:
    - reference_id: file:human/UBAC2/UBAC2-uniprot.txt
      supporting_text: 'Q8NBM4; Q96CS3: FAF2'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: Proteome-scale interactome capture (CALCOCO2). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real interaction from a large-scale interactome but uninformative GO term.
    supported_by:
    - reference_id: file:human/UBAC2/UBAC2-uniprot.txt
      supporting_text: 'Q8NBM4; Q13137: CALCOCO2'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: High-throughput interactome capture of the UBAC2-FAF2 interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real interaction (FAF2) but uninformative GO term.
    supported_by:
    - reference_id: file:human/UBAC2/UBAC2-uniprot.txt
      supporting_text: 'Q8NBM4; Q96CS3: FAF2'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: Multimodal cell-map interactome capture of the UBAC2-FAF2 interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real interaction (FAF2) but uninformative GO term.
    supported_by:
    - reference_id: file:human/UBAC2/UBAC2-uniprot.txt
      supporting_text: 'Q8NBM4; Q96CS3: FAF2'
- term:
    id: GO:0090090
    label: negative regulation of canonical Wnt signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Orthology-based assignment of the negative Wnt-regulation role, consistent with the experimental IMP evidence (LMBR1L/AMFR complex promotes degradation of CTNNB1 and Wnt receptors).
    action: ACCEPT
    reason: Correct biological process; redundant with experimental IMP evidence.
    supported_by:
    - reference_id: PMID:31073040
      supporting_text: attenuated Wnt signaling in lymphocytes
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:39284914
  qualifier: enables
  review:
    summary: IPI interactions from the ER-phagy study (including GABARAP-family/autophagy partners). Bare protein binding is uninformative; the GABARAP binding underpins the ER-phagy receptor function captured by the reticulophagy annotation.
    action: KEEP_AS_NON_CORE
    reason: Real autophagy-partner interactions but uninformative GO term.
    supported_by:
    - reference_id: PMID:39284914
      supporting_text: binds to autophagosomal GABARAP
- term:
    id: GO:0050728
    label: negative regulation of inflammatory response
  evidence_type: IMP
  original_reference_id: PMID:39284914
  qualifier: involved_in
  review:
    summary: By driving ER-phagy, UBAC2 restrains ER-stress-induced inflammatory responses and acute colitis in mice; perturbation of UBAC2 alters the inflammatory response.
    action: ACCEPT
    reason: Directly supported (IMP); a downstream consequence of UBAC2's ER-phagy receptor activity.
    supported_by:
    - reference_id: PMID:39284914
      supporting_text: UBAC2 restrains inflammatory responses and acute ulcerative
- term:
    id: GO:0061709
    label: reticulophagy
  evidence_type: IMP
  original_reference_id: PMID:39284914
  qualifier: involved_in
  review:
    summary: UBAC2 is a selective ER-phagy (reticulophagy) receptor with a LIR motif that binds GABARAP; MARK2-mediated Ser223 phosphorylation drives dimerization and GABARAP binding to mediate selective ER degradation.
    action: ACCEPT
    reason: Directly demonstrated core biological process; UBAC2 functions as an ER-phagy receptor.
    supported_by:
    - reference_id: PMID:39284914
      supporting_text: we identified ubiquitin-associated domain-containing protein 2 (UBAC2) as a receptor for ER-phagy
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31073040
  qualifier: enables
  review:
    summary: IPI capture of the UBAC2-LMBR1L interaction. Bare protein binding is uninformative; the functional cooperation is captured by the negative Wnt-regulation annotation.
    action: KEEP_AS_NON_CORE
    reason: Real interaction (LMBR1L) but uninformative GO term.
    supported_by:
    - reference_id: file:human/UBAC2/UBAC2-uniprot.txt
      supporting_text: Interacts with LMBR1L
- term:
    id: GO:0090090
    label: negative regulation of canonical Wnt signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:31073040
  qualifier: involved_in
  review:
    summary: With LMBR1L and AMFR, UBAC2 negatively regulates canonical Wnt signaling in lymphocytes by promoting ubiquitin-mediated degradation of CTNNB1 and the Wnt receptors FZD6 and LRP6.
    action: ACCEPT
    reason: Directly supported (IMP) biological process; a distinct UBAC2 regulatory role.
    supported_by:
    - reference_id: PMID:31073040
      supporting_text: attenuated Wnt signaling in lymphocytes
- term:
    id: GO:1904153
    label: negative regulation of retrograde protein transport, ER to cytosol
  evidence_type: IMP
  original_reference_id: PMID:25660456
  qualifier: involved_in
  review:
    summary: UBAC2 negatively regulates ER-to-cytosol dislocation/retrotranslocation, consistent with its role as the ER receptor that restricts FAF2/UBXD8 trafficking and modulates ERAD substrate dislocation.
    action: ACCEPT
    reason: Directly supported (IMP); UBAC2 modulates the ER-to-cytosol retrotranslocation step of ERAD.
    supported_by:
    - reference_id: PMID:25660456
      supporting_text: dislocation, also known as retrotranslocation, of those unwanted proteins from
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:23297223
  qualifier: located_in
  review:
    summary: Direct evidence that UBAC2 is an ER-resident protein, the compartment where it acts as an ER receptor for FAF2/UBXD8.
    action: ACCEPT
    reason: Core compartment; directly demonstrated.
    supported_by:
    - reference_id: PMID:23297223
      supporting_text: the ER-resident rhomboid pseudoprotease UBAC2
- term:
    id: GO:0070972
    label: protein localization to endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:23297223
  qualifier: acts_upstream_of_or_within
  review:
    summary: UBAC2 retains FAF2/UBXD8 at the ER (restricting its trafficking to lipid droplets), thereby controlling FAF2 protein localization to the ER.
    action: ACCEPT
    reason: Directly supported; UBAC2 acts as an ER receptor that governs partner localization at the ER.
    supported_by:
    - reference_id: PMID:23297223
      supporting_text: restricts trafficking of UBXD8 to LDs
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: file:human/UBAC2/UBAC2-hypotheses/function-hypothesis-go-0004252/openscientist.md
  title: OpenScientist hypothesis investigation - UBAC2 serine-type endopeptidase activity
  publication_type: DEEP_RESEARCH
  findings:
  - statement: OpenScientist refuted the UBAC2 GO:0004252 serine-type endopeptidase
      activity hypothesis and recommended removing the propagated IBA annotation.
    supporting_text: UBAC2 does not have serine-type endopeptidase activity (GO:0004252).
      The annotation should be removed.
  - statement: The report traced the incorrect IBA to phylogenetic transfer from
      active rhomboid proteases to a catalytically inactive rhomboid pseudoprotease.
    supporting_text: 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.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: OpenScientist autonomous-compute report directly evaluates the contested
      IBA serine-type endopeptidase activity assignment. The report snippets cited
      here were checked as verbatim support, and this curation use is anchored to
      PMID:23297223 and the existing UBAC2 pseudoprotease review rather than relying
      only on the report's self-cited literature summary.
- id: PMID:22119785
  title: Defining human ERAD networks through an integrative mapping strategy.
  findings:
  - statement: UBAC2 interacts with FAF2/UBXD8 within the human ERAD interaction network.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: ERAD interactome mapping; source of a UBAC2-FAF2 IPI annotation.
- id: PMID:23297223
  title: Spatial regulation of UBXD8 and p97/VCP controls ATGL-mediated lipid droplet
    turnover.
  findings:
  - statement: 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.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes UBAC2 as an ER-resident pseudoprotease and FAF2 ER receptor; source of ER localization and protein-localization-to-ER annotations.
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Large-scale interactome; source of a UBAC2-CALCOCO2 IPI annotation.
- id: PMID:25660456
  title: Identification of ERAD components essential for dislocation of the null Hong
    Kong variant of α-1-antitrypsin (NHK).
  findings:
  - statement: ERAD requires dislocation/retrotranslocation of substrates from the ER lumen to the cytosol; UBAC2 negatively regulates this dislocation step.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Source of the IMP negative-regulation-of-ER-to-cytosol-retrograde-transport annotation.
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease
    networks.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; source of a UBAC2-FAF2 IPI annotation.
- id: PMID:31073040
  title: LMBR1L regulates lymphopoiesis through Wnt/β-catenin signaling.
  findings:
  - statement: UBAC2 (with LMBR1L and AMFR) attenuates canonical Wnt/beta-catenin signaling in lymphocytes by promoting degradation of CTNNB1 and Wnt receptors FZD6/LRP6.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes UBAC2's negative regulation of canonical Wnt signaling.
- id: PMID:39284914
  title: ER-phagy restrains inflammatory responses through its receptor UBAC2.
  findings:
  - statement: 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.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Definitive study establishing UBAC2 as an ER-phagy receptor; source of reticulophagy and negative-regulation-of-inflammatory-response annotations.
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Multimodal cell-map interactome; source of a UBAC2-FAF2 IPI annotation.
- id: PMID:22455605
  title: Replication study confirms the association between UBAC2 and Behçet's disease
    in two independent Chinese sets of patients and controls.
  findings:
  - statement: 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.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified (PMID:22455605, doi:10.1186/ar3789). Disease-genetics/regulatory evidence linking UBAC2 to Behçet's disease via a functional promoter polymorphism; supports medical relevance of the locus but does not define UBAC2 protein biochemical mechanism. Not tied to a specific GO annotation.
- id: PMID:21700618
  title: Genome-wide association study identifies novel alleles associated with risk
    of cutaneous basal cell carcinoma and squamous cell carcinoma.
  findings:
  - statement: A variant (rs7335046) at the 13q32 locus near UBAC2 confers susceptibility to cutaneous basal cell carcinoma and squamous cell carcinoma.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: PubMed-verified (PMID:21700618, doi:10.1093/hmg/ddr287). Locus-level GWAS association of the UBAC2 region with non-melanoma skin cancer; medical relevance only, does not establish UBAC2 as the causal effector gene or define function.
- id: file:human/UBAC2/UBAC2-uniprot.txt
  title: UniProt entry Q8NBM4 (UBAC2_HUMAN), ubiquitin-associated domain-containing protein 2
  findings:
  - statement: 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.
    reference_section_type: OTHER
core_functions:
- description: ER-membrane scaffolding/adaptor pseudoprotease of the rhomboid superfamily that, via its cytoplasmic UBA domain, engages ubiquitinated substrates as a component of the ER-associated degradation (ERAD) machinery and acts as the ER receptor restricting FAF2/UBXD8 trafficking from the ER to lipid droplets.
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  directly_involved_in:
  - id: GO:1904153
    label: negative regulation of retrograde protein transport, ER to cytosol
  supported_by:
  - reference_id: PMID:23297223
    supporting_text: the ER-resident rhomboid pseudoprotease UBAC2
  - reference_id: PMID:25660456
    supporting_text: dislocation, also known as retrotranslocation, of those unwanted proteins from
- description: Selective autophagy (ER-phagy/reticulophagy) receptor whose cytoplasmic LIR motif binds autophagosomal GABARAP; MARK2-driven Ser223 phosphorylation promotes dimerization and GABARAP binding to mediate selective ER degradation, thereby restraining ER-stress-induced inflammatory responses.
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  directly_involved_in:
  - id: GO:0061709
    label: reticulophagy
  - id: GO:0050728
    label: negative regulation of inflammatory response
  supported_by:
  - reference_id: PMID:39284914
    supporting_text: we identified ubiquitin-associated domain-containing protein 2 (UBAC2) as a receptor for ER-phagy
  - reference_id: PMID:39284914
    supporting_text: binds to autophagosomal GABARAP
- description: Negative regulator of canonical Wnt/beta-catenin signaling that, in a complex with LMBR1L and the E3 ligase AMFR, promotes ubiquitin-mediated degradation of CTNNB1 and the Wnt receptors FZD6 and LRP6 in lymphocytes.
  directly_involved_in:
  - id: GO:0090090
    label: negative regulation of canonical Wnt signaling pathway
  supported_by:
  - reference_id: PMID:31073040
    supporting_text: attenuated Wnt signaling in lymphocytes
proposed_new_terms: []
suggested_questions:
- question: Does the UBAC2 cytoplasmic UBA domain directly bind ubiquitinated ERAD substrates handed off by the active rhomboid protease RHBDD1, and what substrate range does the RHBDD1-UBAC2 module degrade?
- question: How are UBAC2's ERAD-component, FAF2 ER-receptor, ER-phagy receptor, and Wnt-regulatory activities coordinated or partitioned, and do they share the same UBAC2 pool or distinct membrane microdomains?
suggested_experiments:
- description: Reconstitute or co-immunoprecipitate the RHBDD1-UBAC2 module and test whether UBAC2 UBA-domain mutants lose binding to ubiquitinated membrane ERAD substrates, dissociating the scaffolding role from RHBDD1 catalysis.
- description: Use Ser223-phospho (S223A and S223D) and LIR-motif (W275A/L278A) UBAC2 mutants in ER-phagy flux assays (RFP-GFP ER reporters) with and without ER stress to quantify the contribution of MARK2-driven dimerization to selective ER degradation.
- description: Perform comparative proteomics of UBAC2 interactomes under basal, ER-stress, and starvation conditions to map how its ERAD, ER-phagy, and Wnt-regulatory partner networks are remodeled.

UBAC2

Gene Description

Existing Annotations Review

Core Functions

Selective autophagy (ER-phagy/reticulophagy) receptor whose cytoplasmic LIR motif binds autophagosomal GABARAP; MARK2-driven Ser223 phosphorylation promotes dimerization and GABARAP binding to mediate selective ER degradation, thereby restraining ER-stress-induced inflammatory responses.

Negative regulator of canonical Wnt/beta-catenin signaling that, in a complex with LMBR1L and the E3 ligase AMFR, promotes ubiquitin-mediated degradation of CTNNB1 and the Wnt receptors FZD6 and LRP6 in lymphocytes.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Comprehensive Research Report: Human UBAC2 (UniProt Q8NBM4) — Functional Annotation, Pathways, and Disease Context

Executive summary

1. Key concepts and definitions (current understanding)

1.1 UBAC2 as a rhomboid-like “pseudoprotease”

1.2 UBA domain and ubiquitin-dependent protein quality control

1.3 ERAD (endoplasmic reticulum–associated degradation)

1.4 ER-phagy (reticulophagy) and LIR–ATG8 family interactions

2. Molecular identity verification (critical disambiguation)

3. Protein features, localization, and primary molecular functions

3.1 Subcellular localization

3.2 UBAC2 as an ER-phagy receptor (major 2024 development)

3.3 UBAC2 in ERAD-like ubiquitin-mediated degradation and Wnt pathway attenuation

4. Recent developments and latest research (prioritize 2023–2024)

4.1 2024: UBAC2–MARK2 axis links ER stress to ER-phagy and inflammation

4.2 2023: UBAC2 in updated ER quality-control frameworks

5. Current applications and real-world implementations

5.1 Translational hypothesis generation: inflammation and IBD

5.2 Signaling pathway modulation: Wnt/β-catenin brake

5.3 Human genetics and biomarker context

6. Expert synthesis and analysis (authoritative interpretations)

6.1 UBAC2 as an integrator of ER proteostasis pathways

6.2 Caution on mechanistic specificity vs locus association

7. Relevant statistics and data (selected)

7.1 Behçet’s disease (Chinese Han cohorts) — UBAC2 locus

7.2 Skin cancer GWAS (UBAC2 region)

7.3 2024 ER-phagy functional statistics (selected)

Evidence map (key sources)

Conclusion

URLs and publication dates (selected)

Artifacts

Citations

OpenScientist

UBAC2 Serine-Type Endopeptidase Activity Hypothesis: Final Report

Executive Judgment

Summary

Key Findings

Finding 1: UBAC2 Lacks the Catalytic Machinery for Serine Endopeptidase Activity

Finding 2: UBAC2 Is Missing TM4–TM7 Where Both Catalytic Residues Reside

Finding 3: IBA Over-Annotation Affects Multiple Rhomboid Pseudoproteases

Finding 4: Catalytic Residue Loss Is Ancestral Across All Vertebrates

Finding 5: Primary Literature Explicitly Identifies UBAC2 as a Pseudoprotease

Evidence Matrix

GO Curation Implications

Recommended Action: REMOVE GO:0004252 from UBAC2

Mechanistic Scope

Direct Molecular Function of UBAC2

Separation from Downstream Phenotypes

Conflicts and Alternatives

The Core Conflict: Family Membership vs. Catalytic Competence

No Competing Evidence Supports Protease Activity

Alternative Interpretation: Regulatory Pseudoenzyme

Potential Confounders

Knowledge Gaps

Discriminating Tests

Definitive Experiments

Computational Analyses

Curation Leads

Lead 1: Remove GO:0004252 (serine-type endopeptidase activity) — HIGH PRIORITY

Lead 2: Consider NOT-Qualified Annotation

Lead 3: Add Candidate Positive Annotations

Lead 4: Flag RHBDF2/iRhom2 for Same Correction

Lead 5: Report PANTHER Tree Issue

Evidence Base: Key Literature

Papers Directly Refuting the Hypothesis

Papers Defining UBAC2's Actual Functions

Disease Association Papers (Informative but Not Relevant to MF Annotation)

Limitations

Proposed Follow-up Actions

Immediate Curation Actions