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.
| 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 explicitly characterized as an ER-resident rhomboid pseudoprotease in PMID:23297223. The OpenScientist sequence audit finds the only GxSG-like motif outside the three annotated membrane spans and no membrane catalytic histidine, supporting target-specific loss of the rhomboid catalytic machinery. This contradicts inherited serine endopeptidase activity without excluding its nonproteolytic ER functions. Propagation Review Root cause: PROPAGATION BAD Failure modes: PSEUDO OR SUBACTIVITY LOSS Sources checked: PANTHER:PTN002453758 SUPPORTS SOURCE BUT NOT TARGET Proximate IBA ancestral node verified in the cached GOA WITH/FROM field. Target-specific loss of the catalytic apparatus, documented in the cited primary/sequence evidence, challenges retention of this ancestral reaction. The full PAINT reconstruction was not independently repeated; extant donor count or target self-inclusion is not evidence against the annotation. 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. file:human/UBAC2/UBAC2-hypotheses/function-hypothesis-go-0004252/openscientist.md No GxSG motif exists within the three transmembrane segments of UBAC2 |
| 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 ... | REMOVE | Summary: The cited interaction evidence is retained as context, but the generic protein-binding term does not specify a molecular function. Reason: PMID:22119785 reports protein interactions. Remove this uninformative GO:0005515 assertion under the annotation-reviewer policy; this does not reject the interaction or infer that the experiment assayed the wrong gene. A specific molecular function is not inferred from an interaction screen alone. 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. | REMOVE | Summary: The cited interaction evidence is retained as context, but the generic protein-binding term does not specify a molecular function. Reason: PMID:25416956 reports protein interactions. Remove this uninformative GO:0005515 assertion under the annotation-reviewer policy; this does not reject the interaction or infer that the experiment assayed the wrong gene. A specific molecular function is not inferred from an interaction screen alone. 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... | REMOVE | Summary: The cited interaction evidence is retained as context, but the generic protein-binding term does not specify a molecular function. Reason: PMID:28514442 reports protein interactions. Remove this uninformative GO:0005515 assertion under the annotation-reviewer policy; this does not reject the interaction or infer that the experiment assayed the wrong gene. A specific molecular function is not inferred from an interaction screen alone. 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... | REMOVE | Summary: The cited interaction evidence is retained as context, but the generic protein-binding term does not specify a molecular function. Reason: PMID:40205054 reports protein interactions. Remove this uninformative GO:0005515 assertion under the annotation-reviewer policy; this does not reject the interaction or infer that the experiment assayed the wrong gene. A specific molecular function is not inferred from an interaction screen alone. 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... | MODIFY | Summary: UBAC2 connects the ER membrane to autophagosomal GABARAP through its LIR motif. Reason: Direct interaction, LIR dependence, and selective ER-degradation experiments establish ER-autophagosome adaptor function; this is a supported replacement for generic protein binding. Proposed replacements: endoplasmic reticulum-autophagosome adaptor activity Supporting Evidence: PMID:39284914 UBAC2 harbors a canonical LC3-interacting region (LIR) in its cytoplasmic domain, which binds to autophagosomal GABARAP. PMID:39284914 Dimerized UBAC2 interacts more strongly with GABARAP, thus facilitating selective degradation of the ER. |
| 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 file:human/UBAC2/UBAC2-deep-research-falcon.md UBAC2 contains a **canonical LIR** in its cytosolic domain that binds **GABARAP**. |
| GO:0005515 protein binding | IPI PMID:31073040 LMBR1L regulates lymphopoiesis through Wnt/Ξ²-catenin signali... | REMOVE | Summary: The cited interaction evidence is retained as context, but the generic protein-binding term does not specify a molecular function. Reason: PMID:31073040 reports protein interactions. Remove this uninformative GO:0005515 assertion under the annotation-reviewer policy; this does not reject the interaction or infer that the experiment assayed the wrong gene. A specific molecular function is not inferred from an interaction screen alone. 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/Ξ²-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 |
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Download this section (compressed HTML)Q: 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?
Q: 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?
Experiment: 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.
Experiment: 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.
Experiment: 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.
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