Wolframin (WFS1) is a multi-pass transmembrane glycoprotein primarily localized to the endoplasmic reticulum (ER) membrane and mitochondria-associated ER membranes (MAMs). The protein plays essential roles in ER calcium homeostasis by positively modulating ER Ca2+ levels through increasing the rate of Ca2+ uptake [PMID:16989814]. WFS1 also functions as a negative regulator of ER stress signaling, particularly by suppressing ATF6alpha-mediated unfolded protein response through stabilization of the E3 ubiquitin ligase HRD1 and promotion of ATF6alpha proteasomal degradation [PMID:20160352]. Additionally, WFS1 interacts with and stabilizes V-ATPase subunit ATP6V1A and Na+/K+-ATPase beta1 subunit (ATP1B1), regulating their expression and stability [PMID:23035048, PMID:17947299]. Mutations in WFS1 cause Wolfram syndrome (DIDMOAD - diabetes insipidus, diabetes mellitus, optic atrophy, deafness), characterized by progressive beta-cell loss and neurodegeneration due to dysregulated ER stress and calcium homeostasis.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0030968 endoplasmic reticulum unfolded protein response | IBA GO_REF:0000033 | ACCEPT | Summary: WFS1 is directly involved in the UPR, functioning as a negative regulator of ER stress signaling. WFS1 suppresses expression of ATF6alpha target genes and represses ATF6alpha-mediated activation of the ER stress response element promoter [PMID:20160352]. WFS1 expression is transcriptionally upregulated by ER stress, indicating it is part of the ER stress response machinery [PMID:15994758]. Reason: Core function supported by phylogenetic analysis (IBA) and extensive experimental evidence. WFS1 negatively regulates the UPR through ATF6alpha suppression and is induced by ER stress [PMID:20160352, PMID:15994758]. Supporting Evidence: PMID:20160352 WFS1 negatively regulates a key transcription factor involved in ER stress signaling, activating transcription factor 6alpha (ATF6alpha), through the ubiquitin-proteasome pathway PMID:15994758 WFS1 expression was transcriptionally up-regulated by ER stress-inducing chemical insults file:human/WFS1/WFS1-deep-research-falcon.md model: Edison Scientific Literature |
| GO:0005789 endoplasmic reticulum membrane | IBA GO_REF:0000033 | ACCEPT | Summary: WFS1 is an ER membrane-resident multi-pass transmembrane protein. This localization has been confirmed by multiple studies using immunocytochemistry, subcellular fractionation, and electron microscopy [PMID:14527944, PMID:11181571, PMID:23035048]. Reason: Core localization consistently demonstrated across multiple independent studies. UniProt annotation confirms ER membrane localization with multi-pass topology. Supporting Evidence: PMID:14527944 Endoglycosidase H digestion, immunocytochemistry, and subcellular fractionation studies all indicated that wolframin is localized to the endoplasmic reticulum PMID:11181571 predominant subcellular localization to endoplasmic reticulum in cultured cells |
| GO:0055074 calcium ion homeostasis | IBA GO_REF:0000033 | ACCEPT | Summary: WFS1 participates in the regulation of cellular Ca2+ homeostasis by modulating the filling state of the ER Ca2+ store. Studies demonstrate WFS1 positively modulates ER Ca2+ levels by increasing the rate of Ca2+ uptake, and the magnitude of store-operated Ca2+ entry parallels WFS1 expression levels [PMID:16989814]. Reason: Core function supported by phylogenetic inference and direct experimental evidence. WFS1 regulates ER calcium homeostasis, a central aspect of its physiological role. Supporting Evidence: PMID:16989814 WFS1 protein to positively modulate ER Ca(2+) levels by increasing the rate of Ca(2+) uptake |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000120 | ACCEPT | Summary: IEA annotation inferring ER localization from InterPro domain mapping and orthology. This is consistent with experimental data showing ER localization. Reason: Computational inference consistent with extensive experimental evidence of ER localization [PMID:14527944, PMID:11181571]. The more specific term GO:0005789 (ER membrane) is also correctly annotated. Supporting Evidence: PMID:14527944 wolframin is localized to the endoplasmic reticulum in rat brain hippocampus and rat pancreatic islet beta-cells |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: IEA annotation based on UniProtKB subcellular location mapping. Consistent with experimental evidence and IBA annotation. Reason: Computational annotation correctly reflects the established ER membrane localization of this multi-pass transmembrane protein. Supporting Evidence: PMID:11181571 predominant subcellular localization to endoplasmic reticulum in cultured cells |
| GO:0010468 regulation of gene expression | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA machine learning annotation. While WFS1 does affect gene expression indirectly through its regulation of ATF6alpha signaling, this term is too general and does not capture the mechanistic specificity. Reason: This is an indirect effect of WFS1's role in ER stress signaling. The more specific annotation of negative regulation of ATF6-mediated UPR is more informative. This general term is not wrong but represents an overly broad annotation. |
| GO:0030133 transport vesicle | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: IEA annotation based on UniProtKB subcellular location vocabulary. WFS1 has been shown to localize to secretory granules in addition to ER [PMID:23035048]. Reason: WFS1 localization to secretory granules has been demonstrated, but this is secondary to its primary ER membrane localization. The term captures a valid but non-core aspect of WFS1 localization. Supporting Evidence: PMID:23035048 WFS1 also localizes to secretory granules in human neuroblastoma cells |
| GO:0031410 cytoplasmic vesicle | IEA GO_REF:0000043 | KEEP AS NON CORE | Summary: IEA annotation from UniProtKB keyword mapping. This is consistent with the secretory granule localization observed for WFS1. Reason: A broad term that encompasses the secretory granule localization. Not incorrect but less specific than GO:0030141 (secretory granule). |
| GO:0035556 intracellular signal transduction | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: ARBA machine learning annotation. WFS1 does participate in ER stress signaling, but this term is very broad and non-specific. Reason: This term is too general. WFS1's role in signaling is specifically in negative regulation of ER stress/UPR signaling, which is captured by more specific terms. |
| GO:0055074 calcium ion homeostasis | IEA GO_REF:0000002 | ACCEPT | Summary: IEA annotation from InterPro domain mapping. Consistent with experimental evidence of WFS1's role in calcium homeostasis. Reason: Duplicate with IBA annotation above. Both correctly reflect WFS1's core function in calcium homeostasis. The IBA annotation provides stronger phylogenetic support. Supporting Evidence: PMID:16989814 WFS1 protein participates in the regulation of cellular Ca(2+) homeostasis |
| GO:1902532 negative regulation of intracellular signal transduction | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA annotation. WFS1 does negatively regulate ER stress signaling, but this term is overly broad. Reason: The more specific term GO:1903573 (negative regulation of response to ER stress) better captures WFS1's function. This general term is not wrong but is less informative. |
| GO:1903573 negative regulation of response to endoplasmic reticulum stress | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA annotation correctly identifying WFS1's role as a negative regulator of ER stress response. This is well-supported by experimental evidence [PMID:20160352]. Reason: Core function of WFS1. Directly supported by experimental evidence showing WFS1 negatively regulates ATF6-mediated ER stress signaling. Supporting Evidence: PMID:20160352 WFS1 negatively regulates a key transcription factor involved in ER stress signaling |
| GO:0005515 protein binding | IPI PMID:17947299 Sodium-potassium ATPase 1 subunit is a molecular partner of ... | MODIFY | Summary: IPI based on co-immunoprecipitation showing WFS1 interacts with Na+/K+ ATPase beta1 subunit (ATP1B1). However, 'protein binding' is uninformative. Reason: The generic 'protein binding' term provides no functional insight. This should be replaced with a more specific binding term if available, or the interaction should be captured as part of the stabilization/regulation function. Proposed replacements: ATPase binding Supporting Evidence: PMID:17947299 We confirmed the interaction by co-immunoprecipitation in mammalian cells and with endogenous proteins |
| GO:0005515 protein binding | IPI PMID:21044950 Genome-wide YFP fluorescence complementation screen identifi... | REMOVE | Summary: From genome-wide YFP fluorescence complementation screen for telomere signaling regulators. This is a high-throughput study with potential false positives. Reason: Generic 'protein binding' from high-throughput screen. The connection to telomere signaling is not a core WFS1 function and may represent noise from the screen. Supporting Evidence: PMID:21044950 Epub 2010 Nov 2. Genome-wide YFP fluorescence complementation screen identifies new regulators for telomere signaling in human cells. |
| GO:0005515 protein binding | IPI PMID:25274773 Sarco(endo)plasmic reticulum ATPase is a molecular partner o... | MODIFY | Summary: IPI showing WFS1 interaction with SERCA (ATP2A2). This is a functionally relevant interaction for calcium homeostasis. Reason: Generic 'protein binding' should be replaced with more specific term reflecting the functional significance of SERCA interaction in calcium homeostasis. Proposed replacements: ATPase binding Supporting Evidence: PMID:25274773 Sarco(endo)plasmic reticulum ATPase is a molecular partner of Wolfram syndrome 1 protein, which negatively regulates its expression. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: From reference map of human binary protein interactome. High-throughput interactome study. Reason: Generic 'protein binding' from high-throughput interactome study. Multiple interactors listed without functional validation. Does not provide informative annotation. Supporting Evidence: PMID:32296183 Apr 8. A reference map of the human binary protein interactome. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | REMOVE | Summary: Interactome mapping in neurodegenerative disease context. High-throughput study. Reason: Generic 'protein binding' from high-throughput study. Does not add functional information beyond what is captured by more specific binding annotations. Supporting Evidence: PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains. |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara ortholog transfer. WFS1 indirectly affects transcription through ATF6alpha regulation, but this is not a direct transcriptional regulatory function. Reason: This is an indirect effect mediated through ATF6alpha suppression. WFS1 is not a direct transcriptional regulator but affects transcription through ER stress signaling modulation. |
| GO:0005516 calmodulin binding | IEA GO_REF:0000107 | UNDECIDED | Summary: Ensembl Compara ortholog transfer. WFS1 has EF-hand-like domains that could potentially bind calmodulin, but direct evidence is limited. Reason: The EF-hand-like domain in WFS1 suggests calcium-binding capability, but direct evidence for calmodulin binding is not available in the reviewed literature. Requires experimental validation. |
| GO:0030672 synaptic vesicle membrane | IEA GO_REF:0000107 | UNDECIDED | Summary: Ensembl Compara ortholog transfer. WFS1 is expressed in neurons and localizes to secretory granules, but synaptic vesicle membrane localization is not directly demonstrated for human WFS1. Reason: While WFS1 is expressed in neurons and has been shown in secretory granules, specific synaptic vesicle membrane localization needs direct experimental verification in human cells. |
| GO:0030968 endoplasmic reticulum unfolded protein response | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara ortholog transfer. Consistent with IBA annotation and experimental evidence. Reason: Duplicate of IBA annotation. Core function well-supported by experimental evidence [PMID:20160352]. |
| GO:0031016 pancreas development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara ortholog transfer. WFS1 is expressed in pancreatic beta-cells and mutations cause diabetes, but direct involvement in pancreas development is not established. Reason: WFS1 mutations affect beta-cell survival and function, but this is distinct from a developmental role. The phenotype in Wolfram syndrome is degenerative rather than developmental. |
| GO:0031398 positive regulation of protein ubiquitination | IEA GO_REF:0000120 | ACCEPT | Summary: IEA from combined automated annotation. WFS1 enhances ATF6alpha ubiquitination through HRD1 stabilization [PMID:20160352]. Reason: Core function. WFS1 stabilizes HRD1 E3 ubiquitin ligase and enhances ATF6alpha ubiquitination, directly promoting protein ubiquitination. Supporting Evidence: PMID:20160352 WFS1 stabilized the E3 ubiquitin ligase HRD1, brought ATF6alpha to the proteasome, and enhanced its ubiquitination |
| GO:0031625 ubiquitin protein ligase binding | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara ortholog transfer. WFS1 interacts with and stabilizes the E3 ubiquitin ligase HRD1 [PMID:20160352]. Reason: Core function. WFS1 binds and stabilizes HRD1, an E3 ubiquitin ligase involved in ERAD. This interaction is central to WFS1's function in ER stress regulation. Supporting Evidence: PMID:20160352 WFS1 stabilized the E3 ubiquitin ligase HRD1 |
| GO:0034976 response to endoplasmic reticulum stress | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara ortholog transfer. WFS1 is induced by and responds to ER stress [PMID:15994758]. Reason: Core function. WFS1 expression is induced by ER stress and it functions as a negative regulator of the ER stress response. Supporting Evidence: PMID:15994758 WFS1 expression was transcriptionally up-regulated by ER stress-inducing chemical insults |
| GO:0036503 ERAD pathway | IEA GO_REF:0000120 | ACCEPT | Summary: IEA from combined automated annotation. WFS1 participates in ERAD through HRD1 stabilization and promotion of ATF6alpha degradation [PMID:20160352]. Reason: Core function. WFS1 is involved in ERAD by stabilizing HRD1 and promoting proteasomal degradation of ATF6alpha. Supporting Evidence: PMID:20160352 WFS1 stabilized the E3 ubiquitin ligase HRD1, brought ATF6alpha to the proteasome, and enhanced its ubiquitination and proteasome-mediated degradation |
| GO:0042048 olfactory behavior | IEA GO_REF:0000107 | REMOVE | Summary: Ensembl Compara ortholog transfer. No direct evidence for WFS1 involvement in olfactory behavior in humans. Reason: No literature support for this annotation. Wolfram syndrome phenotype does not include olfactory dysfunction. This may be an over-inference from ortholog data. |
| GO:0045927 positive regulation of growth | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl Compara ortholog transfer. WFS1 affects cell survival through ER stress regulation, but positive regulation of growth is not a core function. Reason: This is likely an indirect effect of WFS1's role in cell survival and ER stress. Not a primary function of the protein. |
| GO:0048306 calcium-dependent protein binding | IEA GO_REF:0000107 | UNDECIDED | Summary: Ensembl Compara ortholog transfer. WFS1 has EF-hand-like domains that may enable calcium-dependent protein interactions. Reason: The EF-hand-like domain suggests potential calcium-dependent binding, but direct experimental evidence for this specific molecular function is not available in the reviewed literature. |
| GO:0050821 protein stabilization | IEA GO_REF:0000120 | ACCEPT | Summary: IEA from combined automated annotation. WFS1 stabilizes V-ATPase subunit ATP6V1A, Na+/K+-ATPase beta1 subunit, and HRD1 [PMID:23035048, PMID:17947299, PMID:20160352]. Reason: Core function. WFS1 stabilizes multiple protein partners through proteasome-independent mechanisms [PMID:23035048]. Supporting Evidence: PMID:23035048 WFS1 protein deficiency affects... Protein stability assays demonstrated that the V1A subunit was degraded more rapidly in WFS1 depleted neuroblastoma cells PMID:20160352 WFS1 stabilized the E3 ubiquitin ligase HRD1 |
| GO:0051117 ATPase binding | IEA GO_REF:0000120 | ACCEPT | Summary: IEA from combined automated annotation. WFS1 interacts with V-ATPase V1A subunit and Na+/K+-ATPase beta1 subunit [PMID:23035048, PMID:17947299]. Reason: Core molecular function. WFS1 binds to and regulates multiple ATPase subunits including V-ATPase and Na+/K+-ATPase. Supporting Evidence: PMID:23035048 We demonstrated a novel interaction between WFS1 and the V1A subunit of the H(+) V-ATPase PMID:17947299 Na+/K+ ATPase beta1 subunit was identified as an interacting clone |
| GO:0070628 proteasome binding | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara ortholog transfer. WFS1 brings ATF6alpha to the proteasome [PMID:20160352], suggesting proteasome interaction. Reason: WFS1 brings substrates to the proteasome for degradation, indicating proteasome binding activity. Supporting Evidence: PMID:20160352 brought ATF6alpha to the proteasome |
| GO:0140297 DNA-binding transcription factor binding | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara ortholog transfer. WFS1 interacts with ATF6alpha, a transcription factor, to promote its degradation [PMID:20160352]. Reason: WFS1 binds to ATF6alpha, a DNA-binding transcription factor, to target it for proteasomal degradation. Supporting Evidence: PMID:20160352 WFS1 negatively regulates a key transcription factor... brought ATF6alpha to the proteasome |
| GO:1902236 negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara ortholog transfer. WFS1 deficiency leads to increased apoptosis through uncontrolled ER stress [PMID:16087305, PMID:20160352]. Reason: WFS1 protects cells from ER stress-induced apoptosis by negatively regulating ER stress signaling. Supporting Evidence: PMID:16087305 we found no increased apoptosis following induction of ER stress but rather by staurosporine treatment in the absence of WFS1 function. This indicates a new role of WFS1 deficiency in programmed cell death |
| GO:1903892 negative regulation of ATF6-mediated unfolded protein response | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara ortholog transfer. This is a core function of WFS1 [PMID:20160352]. Reason: Core function. WFS1 specifically negatively regulates ATF6alpha-mediated UPR through proteasomal degradation of ATF6alpha. Supporting Evidence: PMID:20160352 WFS1 negatively regulates a key transcription factor involved in ER stress signaling, activating transcription factor 6alpha (ATF6alpha) |
| GO:2000675 negative regulation of type B pancreatic cell apoptotic process | IEA GO_REF:0000120 | ACCEPT | Summary: IEA from combined automated annotation. WFS1 deficiency causes beta-cell death in Wolfram syndrome [PMID:16087305]. Reason: Core function in beta-cells. WFS1 protects pancreatic beta-cells from apoptosis, and its deficiency causes progressive beta-cell loss. Supporting Evidence: PMID:16087305 Mice lacking the WFS1 gene display degeneration of pancreatic beta-cells following induction of ER stress |
| GO:0006983 ER overload response | IDA PMID:16989814 WFS1 protein modulates the free Ca(2+) concentration in the ... | ACCEPT | Summary: IDA from direct experiments showing WFS1 modulates ER calcium and is involved in ER stress response [PMID:16989814]. Reason: Core function. WFS1 is involved in ER calcium homeostasis and ER stress response, which includes ER overload response. Supporting Evidence: PMID:16989814 WFS1 protein participates in the regulation of cellular Ca(2+) homeostasis, at least partly, by modulating the filling state of the ER Ca(2+) store |
| GO:0140597 protein carrier chaperone | IDA PMID:20160352 Wolfram syndrome 1 gene negatively regulates ER stress signa... | KEEP AS NON CORE | Summary: IDA annotation. WFS1 brings ATF6alpha to the proteasome for degradation, which could be considered a carrier function. Reason: While WFS1 does transport ATF6alpha to the proteasome, "chaperone" is not the most accurate descriptor. WFS1's primary function is as a negative regulator of ER stress rather than a classic chaperone. Supporting Evidence: PMID:20160352 Wolfram syndrome 1 gene negatively regulates ER stress signaling in rodent and human cells. |
| GO:0031398 positive regulation of protein ubiquitination | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation based on manual transfer from ortholog. Consistent with experimental evidence [PMID:20160352]. Reason: Duplicate of IEA annotation. Core function supported by experimental evidence showing WFS1 enhances ATF6alpha ubiquitination. |
| GO:0031398 positive regulation of protein ubiquitination | IDA PMID:20160352 Wolfram syndrome 1 gene negatively regulates ER stress signa... | ACCEPT | Summary: Direct experimental evidence showing WFS1 enhances ATF6alpha ubiquitination through HRD1 stabilization. Reason: Core function with strong experimental support. Supporting Evidence: PMID:20160352 enhanced its ubiquitination and proteasome-mediated degradation |
| GO:0036503 ERAD pathway | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation. Consistent with experimental evidence of WFS1 role in ERAD. Reason: Duplicate of IEA annotation. Core function in ERAD pathway. |
| GO:0036503 ERAD pathway | IDA PMID:20160352 Wolfram syndrome 1 gene negatively regulates ER stress signa... | ACCEPT | Summary: Direct experimental evidence showing WFS1 participates in ERAD through HRD1 stabilization and ATF6alpha degradation. Reason: Core function with strong experimental support. Supporting Evidence: PMID:20160352 WFS1 stabilized the E3 ubiquitin ligase HRD1, brought ATF6alpha to the proteasome, and enhanced its ubiquitination and proteasome-mediated degradation |
| GO:0005515 protein binding | IPI PMID:23035048 Vacuolar-type H+-ATPase V1A subunit is a molecular partner o... | MODIFY | Summary: IPI showing WFS1 interacts with V-ATPase V1A subunit (ATP6V1A). Functionally relevant interaction. Reason: Generic 'protein binding' should be replaced with more specific term. The interaction with V-ATPase is functionally important. Proposed replacements: ATPase binding Supporting Evidence: PMID:23035048 We demonstrated a novel interaction between WFS1 and the V1A subunit of the H(+) V-ATPase |
| GO:0005783 endoplasmic reticulum | IDA PMID:23035048 Vacuolar-type H+-ATPase V1A subunit is a molecular partner o... | ACCEPT | Summary: Direct experimental evidence confirming ER localization using immunofluorescence and electron microscopy. Reason: Core localization confirmed by multiple experimental approaches. Supporting Evidence: PMID:23035048 immunofluorescent and electron-microscopy analyses confirmed that WFS1 also localizes to secretory granules in human neuroblastoma cells |
| GO:0030141 secretory granule | IDA PMID:23035048 Vacuolar-type H+-ATPase V1A subunit is a molecular partner o... | KEEP AS NON CORE | Summary: Direct experimental evidence showing WFS1 localization to secretory granules in neuroblastoma cells and pancreatic beta-cells. Reason: Valid localization but secondary to primary ER membrane localization. Functionally relevant for V-ATPase interaction in granular acidification. Supporting Evidence: PMID:23035048 immunofluorescent and electron-microscopy analyses confirmed that WFS1 also localizes to secretory granules in human neuroblastoma cells |
| GO:0043066 negative regulation of apoptotic process | IMP PMID:23035048 Vacuolar-type H+-ATPase V1A subunit is a molecular partner o... | ACCEPT | Summary: IMP based on WFS1 depletion experiments showing inverse association between p21 expression and apoptosis. Reason: Core function. WFS1 protects cells from apoptosis through multiple mechanisms including ER stress regulation. Supporting Evidence: PMID:23035048 Cell cycle assays measuring p21(cip) showed reduced levels in WFS1 depleted cells, and an inverse association between p21(cip) expression and apoptosis |
| GO:0050821 protein stabilization | IMP PMID:23035048 Vacuolar-type H+-ATPase V1A subunit is a molecular partner o... | ACCEPT | Summary: IMP showing WFS1 depletion leads to faster degradation of V1A subunit. Reason: Core function. WFS1 stabilizes V-ATPase V1A subunit and other proteins through proteasome-independent mechanisms. Supporting Evidence: PMID:23035048 Protein stability assays demonstrated that the V1A subunit was degraded more rapidly in WFS1 depleted neuroblastoma cells compared with wild-type |
| GO:1903573 negative regulation of response to endoplasmic reticulum stress | IMP PMID:23035048 Vacuolar-type H+-ATPase V1A subunit is a molecular partner o... | ACCEPT | Summary: IMP from WFS1 depletion studies showing effects on ER stress response. Reason: Core function. WFS1 negatively regulates ER stress response, and its depletion leads to dysregulated ER stress signaling. Supporting Evidence: PMID:23035048 WFS1 protein deficiency affects the unfolded protein response |
| GO:0050821 protein stabilization | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation from ortholog transfer. Consistent with experimental evidence. Reason: Duplicate annotation. Core function well-supported. |
| GO:0050821 protein stabilization | IDA PMID:20160352 Wolfram syndrome 1 gene negatively regulates ER stress signa... | ACCEPT | Summary: IDA showing WFS1 stabilizes HRD1 E3 ubiquitin ligase. Reason: Core function. WFS1 stabilizes HRD1, preventing its degradation. Supporting Evidence: PMID:20160352 WFS1 stabilized the E3 ubiquitin ligase HRD1 |
| GO:0050821 protein stabilization | TAS PMID:23710284 Endoplasmic reticulum stress and Parkinson's disease: the ro... | ACCEPT | Summary: TAS annotation from review article on ER stress and HRD1 in neurodegeneration. Reason: Consistent with experimental evidence from multiple primary studies. Supporting Evidence: PMID:23710284 Apr 18. Endoplasmic reticulum stress and Parkinson's disease: the role of HRD1 in averting apoptosis in neurodegenerative disease. |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-8952289 | KEEP AS NON CORE | Summary: Reactome pathway annotation for FAM20C phosphorylation substrates. WFS1 is phosphorylated in the ER lumen. Reason: WFS1 is primarily an ER membrane protein with portions in the lumen. The phosphorylation site is in the luminal portion. This is a valid but secondary localization annotation. |
| GO:0000122 negative regulation of transcription by RNA polymerase II | IDA PMID:20160352 Wolfram syndrome 1 gene negatively regulates ER stress signa... | KEEP AS NON CORE | Summary: IDA showing WFS1 suppresses ATF6alpha target gene expression. Reason: This is an indirect effect of WFS1's negative regulation of ATF6alpha. WFS1 is not a direct transcriptional regulator but affects transcription through ATF6alpha degradation. Supporting Evidence: PMID:20160352 WFS1 suppressed expression of ATF6alpha target genes and repressed ATF6alpha-mediated activation of the ER stress response element (ERSE) promoter |
| GO:0005789 endoplasmic reticulum membrane | NAS PMID:20160352 Wolfram syndrome 1 gene negatively regulates ER stress signa... | ACCEPT | Summary: NAS annotation for ER membrane localization. Consistent with other evidence. Reason: Core localization. Consistent with extensive experimental evidence. Supporting Evidence: PMID:20160352 Wolfram syndrome 1 gene negatively regulates ER stress signaling in rodent and human cells. |
| GO:0031625 ubiquitin protein ligase binding | IDA PMID:20160352 Wolfram syndrome 1 gene negatively regulates ER stress signa... | ACCEPT | Summary: IDA showing WFS1 binds and stabilizes HRD1 E3 ubiquitin ligase. Reason: Core molecular function. WFS1 binds HRD1 and stabilizes it. Supporting Evidence: PMID:20160352 WFS1 stabilized the E3 ubiquitin ligase HRD1 |
| GO:1903892 negative regulation of ATF6-mediated unfolded protein response | IDA PMID:20160352 Wolfram syndrome 1 gene negatively regulates ER stress signa... | ACCEPT | Summary: Direct experimental evidence showing WFS1 negatively regulates ATF6alpha signaling through proteasomal degradation. Reason: Core function with strong experimental support. Supporting Evidence: PMID:20160352 WFS1 negatively regulates a key transcription factor involved in ER stress signaling, activating transcription factor 6alpha (ATF6alpha), through the ubiquitin-proteasome pathway |
| GO:2000675 negative regulation of type B pancreatic cell apoptotic process | IMP PMID:16087305 Expressional and functional studies of Wolframin, the gene f... | ACCEPT | Summary: IMP showing WFS1 deficiency leads to beta-cell degeneration following ER stress. Reason: Core function in beta-cells. WFS1 protects pancreatic beta-cells from apoptosis. Supporting Evidence: PMID:16087305 Mice lacking the WFS1 gene display degeneration of pancreatic beta-cells following induction of ER stress |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-1791169 | ACCEPT | Summary: Reactome pathway annotation for WFS1 expression. Consistent with other evidence. Reason: Core localization. Consistent with extensive experimental evidence. |
| GO:0005783 endoplasmic reticulum | ISS GO_REF:0000024 | ACCEPT | Summary: ISS from ortholog transfer. Consistent with experimental evidence. Reason: Core localization. Multiple annotations with different evidence codes all support ER localization. |
| GO:0034976 response to endoplasmic reticulum stress | IDA PMID:15994758 Endoplasmic reticulum stress induces Wfs1 gene expression in... | ACCEPT | Summary: Direct experimental evidence showing WFS1 expression is induced by ER stress. Reason: Core function. WFS1 is part of the ER stress response machinery. Supporting Evidence: PMID:15994758 WFS1 expression was transcriptionally up-regulated by ER stress-inducing chemical insults |
| GO:0045927 positive regulation of growth | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: ISS from ortholog transfer. WFS1 promotes cell survival but direct positive regulation of growth is not a primary function. Reason: This is an indirect effect. WFS1's primary role is in ER stress regulation and cell survival, not growth regulation per se. |
| GO:0006983 ER overload response | TAS PMID:17947299 Sodium-potassium ATPase 1 subunit is a molecular partner of ... | ACCEPT | Summary: TAS annotation. WFS1 is involved in ER stress response. Reason: Core function. WFS1 is involved in ER homeostasis and stress response. Supporting Evidence: PMID:17947299 Wolframin deficiency increases ER stress |
| GO:0007601 visual perception | IMP PMID:9771706 A gene encoding a transmembrane protein is mutated in patien... | KEEP AS NON CORE | Summary: IMP based on optic atrophy in Wolfram syndrome patients with WFS1 mutations. This is a disease phenotype rather than a direct molecular function. Reason: This reflects the disease phenotype (optic atrophy) in Wolfram syndrome rather than a direct functional role of WFS1 in visual perception. The visual defect is secondary to retinal ganglion cell degeneration. Supporting Evidence: PMID:9771706 A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome). |
| GO:0007605 sensory perception of sound | IMP PMID:17492394 Mutations in the WFS1 gene are a frequent cause of autosomal... | KEEP AS NON CORE | Summary: IMP based on hearing loss associated with WFS1 mutations. Disease phenotype. Reason: This reflects the deafness phenotype in Wolfram syndrome and DFNA6, not a direct role of WFS1 in auditory function. The hearing loss is likely secondary to hair cell or neuronal dysfunction. Supporting Evidence: PMID:17492394 Mutations in the WFS1 gene are a frequent cause of autosomal dominant nonsyndromic low-frequency hearing loss in Japanese. |
| GO:0032469 endoplasmic reticulum calcium ion homeostasis | IDA PMID:16989814 WFS1 protein modulates the free Ca(2+) concentration in the ... | ACCEPT | Summary: Direct experimental evidence showing WFS1 modulates ER Ca2+ levels by increasing the rate of Ca2+ uptake. Reason: Core function. This is more specific than general calcium ion homeostasis and precisely describes WFS1's role in ER calcium regulation. Supporting Evidence: PMID:16989814 WFS1 protein to positively modulate ER Ca(2+) levels by increasing the rate of Ca(2+) uptake |
| GO:0043069 negative regulation of programmed cell death | IMP PMID:9771706 A gene encoding a transmembrane protein is mutated in patien... | ACCEPT | Summary: IMP from WFS1 mutations causing cell death in Wolfram syndrome. Reason: Core function. WFS1 protects cells from apoptosis through ER stress regulation and calcium homeostasis. Supporting Evidence: PMID:9771706 A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome). |
| GO:0043524 negative regulation of neuron apoptotic process | IMP PMID:9771706 A gene encoding a transmembrane protein is mutated in patien... | ACCEPT | Summary: IMP from neurodegeneration in Wolfram syndrome. Reason: Core function in neurons. WFS1 protects neurons from apoptosis, and its deficiency causes neurodegeneration. Supporting Evidence: PMID:9771706 A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome). |
| GO:0051117 ATPase binding | IPI PMID:17947299 Sodium-potassium ATPase 1 subunit is a molecular partner of ... | ACCEPT | Summary: IPI showing WFS1 interacts with Na+/K+ ATPase beta1 subunit. Reason: Core molecular function. WFS1 binds to and stabilizes Na+/K+ ATPase subunits. Supporting Evidence: PMID:17947299 Na+/K+ ATPase beta1 subunit was identified as an interacting clone |
| GO:0051247 positive regulation of protein metabolic process | IDA PMID:17947299 Sodium-potassium ATPase 1 subunit is a molecular partner of ... | KEEP AS NON CORE | Summary: IDA based on WFS1's role in stabilizing ATPase subunits. Reason: This is a broad term. The more specific terms about protein stabilization and ERAD pathway are more informative. Supporting Evidence: PMID:17947299 Oct 18. Sodium-potassium ATPase 1 subunit is a molecular partner of Wolframin, an endoplasmic reticulum protein involved in ER stress. |
| GO:0051928 positive regulation of calcium ion transport | IDA PMID:16989814 WFS1 protein modulates the free Ca(2+) concentration in the ... | ACCEPT | Summary: IDA showing WFS1 positively modulates ER Ca2+ levels by increasing the rate of Ca2+ uptake. Reason: Core function. WFS1 promotes calcium uptake into the ER. Supporting Evidence: PMID:16989814 WFS1 protein to positively modulate ER Ca(2+) levels by increasing the rate of Ca(2+) uptake |
| GO:0001822 kidney development | IMP PMID:9817917 Diabetes insipidus, diabetes mellitus, optic atrophy and dea... | KEEP AS NON CORE | Summary: IMP based on diabetes insipidus in Wolfram syndrome, suggesting kidney dysfunction. Reason: This reflects the diabetes insipidus phenotype, which may indicate a role in kidney function but is not a direct developmental role. More likely reflects cellular dysfunction rather than developmental function. Supporting Evidence: PMID:9817917 Diabetes insipidus, diabetes mellitus, optic atrophy and deafness (DIDMOAD) caused by mutations in a novel gene (wolframin) coding for a predicted transmembrane protein. |
| GO:0003091 renal water homeostasis | IMP PMID:9817917 Diabetes insipidus, diabetes mellitus, optic atrophy and dea... | KEEP AS NON CORE | Summary: IMP based on diabetes insipidus phenotype in Wolfram syndrome. Reason: Reflects the diabetes insipidus phenotype. WFS1 may affect vasopressin secretion or response through its general cellular functions, but this is not a direct molecular function. Supporting Evidence: PMID:9817917 Diabetes insipidus, diabetes mellitus, optic atrophy and deafness (DIDMOAD) caused by mutations in a novel gene (wolframin) coding for a predicted transmembrane protein. |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:11181571 WFS1 (Wolfram syndrome 1) gene product: predominant subcellu... | ACCEPT | Summary: Direct immunocytochemistry evidence showing ER membrane localization. Reason: Core localization with strong experimental support. Supporting Evidence: PMID:11181571 predominant subcellular localization to endoplasmic reticulum in cultured cells |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:14527944 Wolframin expression induces novel ion channel activity in e... | ACCEPT | Summary: IDA from subcellular fractionation and immunocytochemistry studies. Reason: Core localization with strong experimental support. Supporting Evidence: PMID:14527944 wolframin is localized to the endoplasmic reticulum in rat brain hippocampus and rat pancreatic islet beta-cells |
| GO:0007601 visual perception | IMP PMID:9817917 Diabetes insipidus, diabetes mellitus, optic atrophy and dea... | KEEP AS NON CORE | Summary: IMP based on optic atrophy in Wolfram syndrome. Reason: Disease phenotype reflecting neurodegeneration rather than direct function in visual perception. Supporting Evidence: PMID:9817917 Diabetes insipidus, diabetes mellitus, optic atrophy and deafness (DIDMOAD) caused by mutations in a novel gene (wolframin) coding for a predicted transmembrane protein. |
| GO:0030425 dendrite | ISS PMID:11181571 WFS1 (Wolfram syndrome 1) gene product: predominant subcellu... | KEEP AS NON CORE | Summary: ISS suggesting dendritic localization based on neuronal expression. Reason: WFS1 is expressed in neurons and may localize to dendrites, but primary localization is ER membrane. Neuronal expression is important for understanding the neurodegeneration phenotype. Supporting Evidence: PMID:11181571 WFS1 (Wolfram syndrome 1) gene product: predominant subcellular localization to endoplasmic reticulum in cultured cells and neuronal expression in rat brain. |
| GO:0042593 glucose homeostasis | IMP PMID:9817917 Diabetes insipidus, diabetes mellitus, optic atrophy and dea... | KEEP AS NON CORE | Summary: IMP based on diabetes mellitus phenotype in Wolfram syndrome. Reason: Reflects the diabetes phenotype due to beta-cell dysfunction. WFS1 affects glucose homeostasis indirectly through its role in beta-cell survival rather than direct glucose regulation. Supporting Evidence: PMID:9817917 Diabetes insipidus, diabetes mellitus, optic atrophy and deafness (DIDMOAD) caused by mutations in a novel gene (wolframin) coding for a predicted transmembrane protein. |
| GO:0043524 negative regulation of neuron apoptotic process | IMP PMID:9817917 Diabetes insipidus, diabetes mellitus, optic atrophy and dea... | ACCEPT | Summary: IMP from neurodegeneration observed in Wolfram syndrome. Reason: Core function. Duplicate annotation. WFS1 protects neurons from apoptosis. Supporting Evidence: PMID:9817917 Diabetes insipidus, diabetes mellitus, optic atrophy and deafness (DIDMOAD) caused by mutations in a novel gene (wolframin) coding for a predicted transmembrane protein. |
| GO:0050877 nervous system process | IMP PMID:9817917 Diabetes insipidus, diabetes mellitus, optic atrophy and dea... | MARK AS OVER ANNOTATED | Summary: IMP based on neurological symptoms in Wolfram syndrome. Reason: This term is too broad. The neurological effects in Wolfram syndrome are due to neurodegeneration, which is captured by more specific terms about negative regulation of apoptosis. Supporting Evidence: PMID:9817917 Diabetes insipidus, diabetes mellitus, optic atrophy and deafness (DIDMOAD) caused by mutations in a novel gene (wolframin) coding for a predicted transmembrane protein. |
| GO:0055074 calcium ion homeostasis | IDA PMID:14527944 Wolframin expression induces novel ion channel activity in e... | ACCEPT | Summary: Direct experimental evidence showing wolframin expression increases intracellular calcium. Reason: Core function. WFS1 is involved in calcium homeostasis through ion channel activity in ER membranes. Supporting Evidence: PMID:14527944 Wolframin thus appears to be important in the regulation of intracellular Ca2+ homeostasis |
| GO:0005261 monoatomic cation channel activity | NAS | NEW | Summary: Added to align core_functions with existing annotations. Reason: Core function term not present in existing_annotations. Supporting Evidence: PMID:16989814 WFS1 protein to positively modulate ER Ca(2+) levels by increasing the rate of Ca(2+) uptake PMID:14527944 Wolframin thus appears to be important in the regulation of intracellular Ca2+ homeostasis |
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