Tumour necrosis factor receptor superfamily member 21, known as death receptor 6 (DR6), is a type I plasma-membrane receptor with four extracellular cysteine-rich domains, an extensively N- and O-glycosylated juxtamembrane stalk required for surface delivery, a palmitoylated membrane-proximal cysteine, and a cytoplasmic death domain. No ligand has been established and it is generally treated as an orphan receptor. It is expressed on resting T and B lymphocytes and downregulated on activation, and in the nervous system on immature oligodendrocytes and neurons. Loss-of-function studies in mouse define it as a negative regulator: DR6-null CD4+ T cells hyperproliferate in response to T cell receptor stimulation and overproduce Th2 cytokines, DR6-null B cells overproliferate and resist apoptosis with enlarged germinal centres and elevated antibody titres, and DR6-null or antibody-blocked oligodendrocytes mature and myelinate more readily, with enhanced remyelination after demyelinating injury. DR6 also partners the p75 neurotrophin receptor in the surface complex through which amyloid-beta kills cortical neurons, and forced overexpression drives a Bax-dependent, caspase-8-independent mitochondrial apoptotic route. Two prominent neuronal roles are unresolved. The proposal that DR6 is the receptor for a shed N-terminal fragment of amyloid precursor protein and thereby drives developmental axon pruning and neuronal death rests on a paper retracted in 2024; a physical DR6-APP interaction and a shared genetic requirement for retinal axon pruning are still reported, but the beta-secretase-dependent mechanism is withdrawn. Separately, a report that DR6 drives Wallerian degeneration and Schwann cell remodelling in injured peripheral nerve was not reproduced in two independent knockout lines, including the original one.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: DR6 is a type I transmembrane TNFRSF member displayed at the cell surface; plasma membrane localisation is confirmed by immunofluorescence, by mutagenesis that traps the protein intracellularly, and by orthology. Reason: Correct and well-corroborated primary location, asserted by six independent annotation routes (IBA, ISS, two IDA sources, an Ensembl-based IEA and Reactome TAS). Unaffected by any of the disputes surrounding this gene's neuronal role. Supporting Evidence: PMID:19654028 Deletion of the entire linker region between CRDs and the transmembrane domain, spanning over 130 amino acids, severely compromises the plasma membrane localization of DR6 and leads to its intracellular retention. PMID:19654028 In this study we document that DR6 is an extensively posttranslationally modified transmembrane protein |
| GO:0002250 adaptive immune response | IBA GO_REF:0000033 | ACCEPT | Summary: Dr6-null mice show altered adaptive immune responses: CD4+ T cell hyperproliferation with Th2 skewing, and B cell hyperproliferation with enhanced germinal centre formation and antibody titres. Reason: Correct, though a grouping-level term; the informative statements are the negative-regulation children that this gene also carries. Grounded in two independent mouse knockout studies that are untouched by the retraction of PMID:19225519 or by the Wallerian non-replication in PMID:41891813. Supporting Evidence: PMID:11485735 DR6, therefore, functions as a regulatory receptor for mediating CD4(+) T cell activation and maintaining proper immune responses. PMID:12515813 DR6(-/-) mice exhibited enhanced germinal center formation and increased titers of immunoglobulins to T-dependent as well as T-independent type I and II antigens. |
| GO:0006959 humoral immune response | IBA GO_REF:0000033 | ACCEPT | Summary: Dr6-null mice mount elevated antibody responses to both T-dependent and T-independent antigens. Reason: Correct; an organism-level readout of the B cell regulatory role rather than a distinct molecular activity, but properly supported by the knockout phenotype. Supporting Evidence: PMID:12515813 DR6(-/-) mice exhibited enhanced germinal center formation and increased titers of immunoglobulins to T-dependent as well as T-independent type I and II antigens. |
| GO:0030889 negative regulation of B cell proliferation | IBA GO_REF:0000033 | ACCEPT | Summary: DR6 restrains B cell proliferation: DR6-deficient B cells overproliferate in response to BCR, CD40 and LPS stimulation. Reason: Core biological process, and one of the best-supported statements about this gene. The direction of the effect is explicit in the knockout data. Supporting Evidence: PMID:12515813 In vitro, DR6(-/-) B cells undergo increased proliferation in response to anti-immunoglobulin M, anti-CD40, and lipopolysaccharide. PMID:12515813 This is the first demonstration of a regulatory role of DR6 in the activation and function of B cells. |
| GO:0031642 negative regulation of myelination | IBA GO_REF:0000033 | ACCEPT | Summary: DR6 is a negative regulator of oligodendrocyte maturation and myelination; blocking or deleting DR6 enhances myelination and remyelination. Reason: Core biological process in the CNS glial context, and the correctly signed term. Established with three independent manipulations - overexpression, antagonist antibody and germline null - in two demyelination models. Independent of both the retracted APP/DR6 work and the Wallerian non-replication. Supporting Evidence: PMID:21725297 Here we show that death receptor 6 (DR6) is a negative regulator of oligodendrocyte maturation. PMID:21725297 Attenuation of DR6 function leads to enhanced oligodendrocyte maturation, myelination and downregulation of casp3. PMID:21725297 Consistent with the DR6 antagoinst antibody studies, DR6-null mice show enhanced remyelination in both demyelination models. |
| GO:0042130 negative regulation of T cell proliferation | IBA GO_REF:0000033 | ACCEPT | Summary: DR6 restrains CD4+ T cell proliferation: DR6-deficient CD4+ T cells hyperproliferate after TCR stimulation and antigen challenge. Reason: Core biological process, from the founding DR6 knockout study. Supporting Evidence: PMID:11485735 However, DR6(-/-) CD4(+) T cells hyperproliferated in response to TCR-mediated stimulation and protein antigen challenge. PMID:11485735 DR6, therefore, functions as a regulatory receptor for mediating CD4(+) T cell activation and maintaining proper immune responses. |
| GO:0051402 neuron apoptotic process | IBA GO_REF:0000033 | ACCEPT | Summary: DR6 participates in neuronal death in a specific pathological context: it binds p75NTR and is a component of the complex that mediates amyloid-beta-induced cortical neuron death. Reason: Kept, and the provenance matters. The high-profile claim that DR6 drives developmental neuronal death as an APP receptor comes from PMID:19225519, which was retracted in 2024 (PMID:38110576) - but no GO annotation on this gene, in human or in the mouse ortholog Q9EPU5 that donates the ISS/IEA transfers, cites that paper. The actual experimental source behind the mouse annotation is PMID:23559013, in which DR6-null cortical neurons are resistant to amyloid-beta neurotoxicity; that work is independent of the retraction. PMID:41891813 (eLife 2026) is also not a counter-argument here: it addresses injury-induced Wallerian degeneration of peripheral axons and Schwann cell responses, which is a different process from neuronal apoptosis and a different compartment from the cortical neurons assayed in PMID:23559013. Two caveats are recorded rather than acted on: the supporting evidence is a pathological rather than a physiological setting, and the retraction notice's continuing affirmation that DR6 and APP control neuron death rests on work by the retracting authors themselves. Supporting Evidence: PMID:23559013 Here, we demonstrate that death receptor 6 (DR6) binds to p75(NTR) and is a component of the p75(NTR) signaling complex responsible for AΞ²-induced cortical neuron death. PMID:23559013 Cortical neurons isolated from either DR6 or p75(NTR) null mice are resistant to AΞ²-induced neurotoxicity. |
| GO:0097252 oligodendrocyte apoptotic process | IBA GO_REF:0000033 | ACCEPT | Summary: DR6 overexpression in oligodendrocytes activates caspase 3 and causes cell death; attenuating DR6 downregulates caspase 3. Reason: Supported by matched gain- and loss-of-function in the ortholog, and consistent with the negative regulation of oligodendrocyte maturation that this gene also carries. Supporting Evidence: PMID:21725297 Overexpression of DR6 in oligodendrocytes leads to caspase 3 (casp3) activation and cell death. PMID:21725297 Attenuation of DR6 function leads to enhanced oligodendrocyte maturation, myelination and downregulation of casp3. |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: DR6 is a type I transmembrane TNFRSF member displayed at the cell surface; plasma membrane localisation is confirmed by immunofluorescence, by mutagenesis that traps the protein intracellularly, and by orthology. Reason: Correct and well-corroborated primary location, asserted by six independent annotation routes (IBA, ISS, two IDA sources, an Ensembl-based IEA and Reactome TAS). Unaffected by any of the disputes surrounding this gene's neuronal role. Supporting Evidence: PMID:19654028 Deletion of the entire linker region between CRDs and the transmembrane domain, spanning over 130 amino acids, severely compromises the plasma membrane localization of DR6 and leads to its intracellular retention. PMID:19654028 In this study we document that DR6 is an extensively posttranslationally modified transmembrane protein |
| GO:0007165 signal transduction | IEA GO_REF:0000002 | ACCEPT | Summary: Generic signal transduction, assigned electronically from the InterPro TNFR cysteine-rich domain signature. Reason: Correct in kind - DR6 is a bona fide transmembrane signalling receptor with CRDs and a cytoplasmic death domain - but carries essentially no information. It is subsumed by the specific regulatory processes annotated elsewhere on this gene. |
| GO:0005515 protein binding | IPI PMID:23559013 A DR6/p75(NTR) complex is responsible for Ξ²-amyloid-induced ... | REMOVE | Summary: Bare protein binding from IntAct, recording physical interactions with p75NTR (P08138), SGTA (O43765), APP (P05067) and PI16 (Q6UXB8). Reason: No more informative molecular function is supportable from this evidence, so the row is removed rather than rewritten. Worth noting what is buried here: the APP interaction (PMID:35922511, with UniProtKB:P05067) is the only trace in GOA of the APP- receptor model, it is recorded only as generic protein binding, and it was redetected in a systematic extracellular-interactome screen entirely independent of the retracted PMID:19225519. The interaction therefore has support that the retraction does not remove, even though the mechanistic model built on it - beta-secretase-dependent shedding of an N-terminal APP fragment - was explicitly among the conclusions withdrawn. A specific amyloid-beta precursor protein binding molecular function, if one is created, would be more informative than either the bare term or silence.'. Removal does not imply the reported interaction is false. Supporting Evidence: PMID:38110576 that DR6 and APP interact and function in a genetic pathway involving caspases to control axon pruning and neuron death PMID:38110576 However, our later research also showed that certain conclusions reached in the article were incorrect, notably the role of caspase-3, the necessity for beta-secretase enzyme activity for APP-DR6 binding, and the model for the APP-DR6 interaction PMID:24806670 further genetic and biochemical analysis reveals that Ξ²-secretase activity is not required and that high-affinity binding to DR6 requires a more C-terminal portion of the APP ectodomain |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Bare protein binding from IntAct, recording physical interactions with p75NTR (P08138), SGTA (O43765), APP (P05067) and PI16 (Q6UXB8). Reason: No more informative molecular function is supportable from this evidence, so the row is removed rather than rewritten. Worth noting what is buried here: the APP interaction (PMID:35922511, with UniProtKB:P05067) is the only trace in GOA of the APP- receptor model, it is recorded only as generic protein binding, and it was redetected in a systematic extracellular-interactome screen entirely independent of the retracted PMID:19225519. The interaction therefore has support that the retraction does not remove, even though the mechanistic model built on it - beta-secretase-dependent shedding of an N-terminal APP fragment - was explicitly among the conclusions withdrawn. A specific amyloid-beta precursor protein binding molecular function, if one is created, would be more informative than either the bare term or silence.'. Removal does not imply the reported interaction is false. Supporting Evidence: PMID:38110576 that DR6 and APP interact and function in a genetic pathway involving caspases to control axon pruning and neuron death PMID:38110576 However, our later research also showed that certain conclusions reached in the article were incorrect, notably the role of caspase-3, the necessity for beta-secretase enzyme activity for APP-DR6 binding, and the model for the APP-DR6 interaction PMID:24806670 further genetic and biochemical analysis reveals that Ξ²-secretase activity is not required and that high-affinity binding to DR6 requires a more C-terminal portion of the APP ectodomain |
| GO:0005515 protein binding | IPI PMID:35922511 A physical wiring diagram for the human immune system. | REMOVE | Summary: Bare protein binding from IntAct, recording physical interactions with p75NTR (P08138), SGTA (O43765), APP (P05067) and PI16 (Q6UXB8). Reason: No more informative molecular function is supportable from this evidence, so the row is removed rather than rewritten. Worth noting what is buried here: the APP interaction (PMID:35922511, with UniProtKB:P05067) is the only trace in GOA of the APP- receptor model, it is recorded only as generic protein binding, and it was redetected in a systematic extracellular-interactome screen entirely independent of the retracted PMID:19225519. The interaction therefore has support that the retraction does not remove, even though the mechanistic model built on it - beta-secretase-dependent shedding of an N-terminal APP fragment - was explicitly among the conclusions withdrawn. A specific amyloid-beta precursor protein binding molecular function, if one is created, would be more informative than either the bare term or silence.'. Removal does not imply the reported interaction is false. Supporting Evidence: PMID:38110576 that DR6 and APP interact and function in a genetic pathway involving caspases to control axon pruning and neuron death PMID:38110576 However, our later research also showed that certain conclusions reached in the article were incorrect, notably the role of caspase-3, the necessity for beta-secretase enzyme activity for APP-DR6 binding, and the model for the APP-DR6 interaction PMID:24806670 further genetic and biochemical analysis reveals that Ξ²-secretase activity is not required and that high-affinity binding to DR6 requires a more C-terminal portion of the APP ectodomain |
| GO:0001783 B cell apoptotic process | IEA GO_REF:0000107 | ACCEPT | Summary: Reduced B cell apoptosis contributes to the hyperproliferative phenotype of DR6-deficient B cells. Reason: Supported by the mouse knockout, in which the increased B cell expansion was attributed partly to reduced apoptosis alongside increased division. Supporting Evidence: PMID:12515813 In vitro, DR6(-/-) B cells undergo increased proliferation in response to anti-immunoglobulin M, anti-CD40, and lipopolysaccharide. |
| GO:0002250 adaptive immune response | IEA GO_REF:0000107 | ACCEPT | Summary: Dr6-null mice show altered adaptive immune responses: CD4+ T cell hyperproliferation with Th2 skewing, and B cell hyperproliferation with enhanced germinal centre formation and antibody titres. Reason: Correct, though a grouping-level term; the informative statements are the negative-regulation children that this gene also carries. Grounded in two independent mouse knockout studies that are untouched by the retraction of PMID:19225519 or by the Wallerian non-replication in PMID:41891813. Supporting Evidence: PMID:11485735 DR6, therefore, functions as a regulatory receptor for mediating CD4(+) T cell activation and maintaining proper immune responses. PMID:12515813 DR6(-/-) mice exhibited enhanced germinal center formation and increased titers of immunoglobulins to T-dependent as well as T-independent type I and II antigens. |
| GO:0006959 humoral immune response | IEA GO_REF:0000107 | ACCEPT | Summary: Dr6-null mice mount elevated antibody responses to both T-dependent and T-independent antigens. Reason: Correct; an organism-level readout of the B cell regulatory role rather than a distinct molecular activity, but properly supported by the knockout phenotype. Supporting Evidence: PMID:12515813 DR6(-/-) mice exhibited enhanced germinal center formation and increased titers of immunoglobulins to T-dependent as well as T-independent type I and II antigens. |
| GO:0007413 axonal fasciculation | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Axonal fasciculation, transferred electronically from an experimental annotation on the rat ortholog. Reason: Two independent reasons for doubt. First, the term looks mismatched to its source: the human row is an Ensembl Compara transfer (GO_REF:0000107) from rat D3ZF92, whose only basis is an IMP from PMID:25898930, a study of prion-peptide-induced axonal degeneration in cultured rat spinal neurons; GO:0007413 is defined as the collection of axons into a bundle of rods known as a fascicle, which that study does not address. Second, the underlying biology - DR6-dependent axon degeneration - is exactly what PMID:41891813 failed to reproduce, using two independent knockout lines including the original one, both in vivo and in axotomised cultures. The rat experimental annotation itself is not overruled here, since its curator read a full text that this review has not; what is flagged is the human electronic annotation that propagates it, which is the only axon-related term this gene carries and the only place in this file where the 2026 non-replication has any purchase. Supporting Evidence: PMID:41891813 Surprisingly, in contrast to the earlier report, we observed no impact of DR6 deletion on AxD kinetics or SC injury responses across a range of WD assays. PMID:41891813 Moreover, injured axons in primary neuronal cultures lacking DR6 degenerated at a similar rate as wild-type axons. |
| GO:0030889 negative regulation of B cell proliferation | IEA GO_REF:0000107 | ACCEPT | Summary: DR6 restrains B cell proliferation: DR6-deficient B cells overproliferate in response to BCR, CD40 and LPS stimulation. Reason: Core biological process, and one of the best-supported statements about this gene. The direction of the effect is explicit in the knockout data. Supporting Evidence: PMID:12515813 In vitro, DR6(-/-) B cells undergo increased proliferation in response to anti-immunoglobulin M, anti-CD40, and lipopolysaccharide. PMID:12515813 This is the first demonstration of a regulatory role of DR6 in the activation and function of B cells. |
| GO:0032693 negative regulation of interleukin-10 production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Elevated IL-10 among the Th2 cytokines overproduced by DR6-deficient CD4+ T cells. Reason: A cytokine readout of the Th2 skewing seen in the DR6 knockout, i.e. a downstream consequence of the T cell regulatory role, not a separate function of the receptor. Supporting Evidence: PMID:11485735 Enhanced Th2 cytokine production by activated DR6(-/-) CD4(+) T cells was associated with the increased transcription factor NF-ATc in nuclei. |
| GO:0032696 negative regulation of interleukin-13 production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Elevated IL-13 among the Th2 cytokines overproduced by DR6-deficient CD4+ T cells. Reason: A cytokine readout of the Th2 skewing seen in the DR6 knockout, i.e. a downstream consequence of the T cell regulatory role, not a separate function of the receptor. Supporting Evidence: PMID:11485735 Enhanced Th2 cytokine production by activated DR6(-/-) CD4(+) T cells was associated with the increased transcription factor NF-ATc in nuclei. |
| GO:0032714 negative regulation of interleukin-5 production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Elevated IL-5 among the Th2 cytokines overproduced by DR6-deficient CD4+ T cells. Reason: A cytokine readout of the Th2 skewing seen in the DR6 knockout, i.e. a downstream consequence of the T cell regulatory role, not a separate function of the receptor. Supporting Evidence: PMID:11485735 Enhanced Th2 cytokine production by activated DR6(-/-) CD4(+) T cells was associated with the increased transcription factor NF-ATc in nuclei. |
| GO:0042130 negative regulation of T cell proliferation | IEA GO_REF:0000107 | ACCEPT | Summary: DR6 restrains CD4+ T cell proliferation: DR6-deficient CD4+ T cells hyperproliferate after TCR stimulation and antigen challenge. Reason: Core biological process, from the founding DR6 knockout study. Supporting Evidence: PMID:11485735 However, DR6(-/-) CD4(+) T cells hyperproliferated in response to TCR-mediated stimulation and protein antigen challenge. PMID:11485735 DR6, therefore, functions as a regulatory receptor for mediating CD4(+) T cell activation and maintaining proper immune responses. |
| GO:0042552 myelination | IEA GO_REF:0000107 | MODIFY | Summary: Unqualified myelination term propagated from the mouse ortholog. Reason: Correct in kind but the direction is wrong to omit: DR6 does not promote myelination, it restrains it. The evidence is that attenuating or deleting DR6 enhances myelination and remyelination. The gene already carries the correctly signed child, which should be the only myelination-related term retained. Proposed replacements: negative regulation of myelination Supporting Evidence: PMID:21725297 Attenuation of DR6 function leads to enhanced oligodendrocyte maturation, myelination and downregulation of casp3. PMID:21725297 Consistent with the DR6 antagoinst antibody studies, DR6-null mice show enhanced remyelination in both demyelination models. |
| GO:0048713 regulation of oligodendrocyte differentiation | IEA GO_REF:0000107 | ACCEPT | Summary: DR6 is expressed strongly in immature oligodendrocytes and weakly in mature ones, and restrains their differentiation. Reason: Correct and appropriately specific; the regulatory term matches the loss- and gain-of-function data. Supporting Evidence: PMID:21725297 Here we show that death receptor 6 (DR6) is a negative regulator of oligodendrocyte maturation. PMID:21725297 Attenuation of DR6 function leads to enhanced oligodendrocyte maturation, myelination and downregulation of casp3. |
| GO:0050852 T cell receptor signaling pathway | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: DR6 modulates the proliferative outcome of T cell receptor stimulation but is not itself a component of the TCR signalling cascade. Reason: Real but peripheral and arguably mis-framed. The evidence is that DR6-null CD4+ T cells respond excessively to TCR-mediated stimulation, which makes DR6 a parallel restraining receptor acting on the same cells, not a participant in the TCR pathway. The negative regulation of T cell proliferation term expresses the same observation more accurately. Supporting Evidence: PMID:11485735 However, DR6(-/-) CD4(+) T cells hyperproliferated in response to TCR-mediated stimulation and protein antigen challenge. |
| GO:0051402 neuron apoptotic process | IEA GO_REF:0000107 | ACCEPT | Summary: DR6 participates in neuronal death in a specific pathological context: it binds p75NTR and is a component of the complex that mediates amyloid-beta-induced cortical neuron death. Reason: Kept, and the provenance matters. The high-profile claim that DR6 drives developmental neuronal death as an APP receptor comes from PMID:19225519, which was retracted in 2024 (PMID:38110576) - but no GO annotation on this gene, in human or in the mouse ortholog Q9EPU5 that donates the ISS/IEA transfers, cites that paper. The actual experimental source behind the mouse annotation is PMID:23559013, in which DR6-null cortical neurons are resistant to amyloid-beta neurotoxicity; that work is independent of the retraction. PMID:41891813 (eLife 2026) is also not a counter-argument here: it addresses injury-induced Wallerian degeneration of peripheral axons and Schwann cell responses, which is a different process from neuronal apoptosis and a different compartment from the cortical neurons assayed in PMID:23559013. Two caveats are recorded rather than acted on: the supporting evidence is a pathological rather than a physiological setting, and the retraction notice's continuing affirmation that DR6 and APP control neuron death rests on work by the retracting authors themselves. Supporting Evidence: PMID:23559013 Here, we demonstrate that death receptor 6 (DR6) binds to p75(NTR) and is a component of the p75(NTR) signaling complex responsible for AΞ²-induced cortical neuron death. PMID:23559013 Cortical neurons isolated from either DR6 or p75(NTR) null mice are resistant to AΞ²-induced neurotoxicity. |
| GO:0097252 oligodendrocyte apoptotic process | IEA GO_REF:0000107 | ACCEPT | Summary: DR6 overexpression in oligodendrocytes activates caspase 3 and causes cell death; attenuating DR6 downregulates caspase 3. Reason: Supported by matched gain- and loss-of-function in the ortholog, and consistent with the negative regulation of oligodendrocyte maturation that this gene also carries. Supporting Evidence: PMID:21725297 Overexpression of DR6 in oligodendrocytes leads to caspase 3 (casp3) activation and cell death. PMID:21725297 Attenuation of DR6 function leads to enhanced oligodendrocyte maturation, myelination and downregulation of casp3. |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | ACCEPT | Summary: DR6 is a type I transmembrane TNFRSF member displayed at the cell surface; plasma membrane localisation is confirmed by immunofluorescence, by mutagenesis that traps the protein intracellularly, and by orthology. Reason: Correct and well-corroborated primary location, asserted by six independent annotation routes (IBA, ISS, two IDA sources, an Ensembl-based IEA and Reactome TAS). Unaffected by any of the disputes surrounding this gene's neuronal role. Supporting Evidence: PMID:19654028 Deletion of the entire linker region between CRDs and the transmembrane domain, spanning over 130 amino acids, severely compromises the plasma membrane localization of DR6 and leads to its intracellular retention. PMID:19654028 In this study we document that DR6 is an extensively posttranslationally modified transmembrane protein |
| GO:0001783 B cell apoptotic process | ISS GO_REF:0000024 | ACCEPT | Summary: Reduced B cell apoptosis contributes to the hyperproliferative phenotype of DR6-deficient B cells. Reason: Supported by the mouse knockout, in which the increased B cell expansion was attributed partly to reduced apoptosis alongside increased division. Supporting Evidence: PMID:12515813 In vitro, DR6(-/-) B cells undergo increased proliferation in response to anti-immunoglobulin M, anti-CD40, and lipopolysaccharide. |
| GO:0002250 adaptive immune response | ISS GO_REF:0000024 | ACCEPT | Summary: Dr6-null mice show altered adaptive immune responses: CD4+ T cell hyperproliferation with Th2 skewing, and B cell hyperproliferation with enhanced germinal centre formation and antibody titres. Reason: Correct, though a grouping-level term; the informative statements are the negative-regulation children that this gene also carries. Grounded in two independent mouse knockout studies that are untouched by the retraction of PMID:19225519 or by the Wallerian non-replication in PMID:41891813. Supporting Evidence: PMID:11485735 DR6, therefore, functions as a regulatory receptor for mediating CD4(+) T cell activation and maintaining proper immune responses. PMID:12515813 DR6(-/-) mice exhibited enhanced germinal center formation and increased titers of immunoglobulins to T-dependent as well as T-independent type I and II antigens. |
| GO:0005886 plasma membrane | ISS GO_REF:0000024 | ACCEPT | Summary: DR6 is a type I transmembrane TNFRSF member displayed at the cell surface; plasma membrane localisation is confirmed by immunofluorescence, by mutagenesis that traps the protein intracellularly, and by orthology. Reason: Correct and well-corroborated primary location, asserted by six independent annotation routes (IBA, ISS, two IDA sources, an Ensembl-based IEA and Reactome TAS). Unaffected by any of the disputes surrounding this gene's neuronal role. Supporting Evidence: PMID:19654028 Deletion of the entire linker region between CRDs and the transmembrane domain, spanning over 130 amino acids, severely compromises the plasma membrane localization of DR6 and leads to its intracellular retention. PMID:19654028 In this study we document that DR6 is an extensively posttranslationally modified transmembrane protein |
| GO:0005886 plasma membrane | IDA PMID:19654028 Functional analysis of the posttranslational modifications o... | ACCEPT | Summary: DR6 is a type I transmembrane TNFRSF member displayed at the cell surface; plasma membrane localisation is confirmed by immunofluorescence, by mutagenesis that traps the protein intracellularly, and by orthology. Reason: Correct and well-corroborated primary location, asserted by six independent annotation routes (IBA, ISS, two IDA sources, an Ensembl-based IEA and Reactome TAS). Unaffected by any of the disputes surrounding this gene's neuronal role. Supporting Evidence: PMID:19654028 Deletion of the entire linker region between CRDs and the transmembrane domain, spanning over 130 amino acids, severely compromises the plasma membrane localization of DR6 and leads to its intracellular retention. PMID:19654028 In this study we document that DR6 is an extensively posttranslationally modified transmembrane protein |
| GO:0006959 humoral immune response | ISS GO_REF:0000024 | ACCEPT | Summary: Dr6-null mice mount elevated antibody responses to both T-dependent and T-independent antigens. Reason: Correct; an organism-level readout of the B cell regulatory role rather than a distinct molecular activity, but properly supported by the knockout phenotype. Supporting Evidence: PMID:12515813 DR6(-/-) mice exhibited enhanced germinal center formation and increased titers of immunoglobulins to T-dependent as well as T-independent type I and II antigens. |
| GO:0030889 negative regulation of B cell proliferation | ISS GO_REF:0000024 | ACCEPT | Summary: DR6 restrains B cell proliferation: DR6-deficient B cells overproliferate in response to BCR, CD40 and LPS stimulation. Reason: Core biological process, and one of the best-supported statements about this gene. The direction of the effect is explicit in the knockout data. Supporting Evidence: PMID:12515813 In vitro, DR6(-/-) B cells undergo increased proliferation in response to anti-immunoglobulin M, anti-CD40, and lipopolysaccharide. PMID:12515813 This is the first demonstration of a regulatory role of DR6 in the activation and function of B cells. |
| GO:0031642 negative regulation of myelination | IMP PMID:21725297 Death receptor 6 negatively regulates oligodendrocyte surviv... | ACCEPT | Summary: DR6 is a negative regulator of oligodendrocyte maturation and myelination; blocking or deleting DR6 enhances myelination and remyelination. Reason: Core biological process in the CNS glial context, and the correctly signed term. Established with three independent manipulations - overexpression, antagonist antibody and germline null - in two demyelination models. Independent of both the retracted APP/DR6 work and the Wallerian non-replication. Supporting Evidence: PMID:21725297 Here we show that death receptor 6 (DR6) is a negative regulator of oligodendrocyte maturation. PMID:21725297 Attenuation of DR6 function leads to enhanced oligodendrocyte maturation, myelination and downregulation of casp3. PMID:21725297 Consistent with the DR6 antagoinst antibody studies, DR6-null mice show enhanced remyelination in both demyelination models. |
| GO:0032693 negative regulation of interleukin-10 production | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Elevated IL-10 among the Th2 cytokines overproduced by DR6-deficient CD4+ T cells. Reason: A cytokine readout of the Th2 skewing seen in the DR6 knockout, i.e. a downstream consequence of the T cell regulatory role, not a separate function of the receptor. Supporting Evidence: PMID:11485735 Enhanced Th2 cytokine production by activated DR6(-/-) CD4(+) T cells was associated with the increased transcription factor NF-ATc in nuclei. |
| GO:0032696 negative regulation of interleukin-13 production | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Elevated IL-13 among the Th2 cytokines overproduced by DR6-deficient CD4+ T cells. Reason: A cytokine readout of the Th2 skewing seen in the DR6 knockout, i.e. a downstream consequence of the T cell regulatory role, not a separate function of the receptor. Supporting Evidence: PMID:11485735 Enhanced Th2 cytokine production by activated DR6(-/-) CD4(+) T cells was associated with the increased transcription factor NF-ATc in nuclei. |
| GO:0032714 negative regulation of interleukin-5 production | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Elevated IL-5 among the Th2 cytokines overproduced by DR6-deficient CD4+ T cells. Reason: A cytokine readout of the Th2 skewing seen in the DR6 knockout, i.e. a downstream consequence of the T cell regulatory role, not a separate function of the receptor. Supporting Evidence: PMID:11485735 Enhanced Th2 cytokine production by activated DR6(-/-) CD4(+) T cells was associated with the increased transcription factor NF-ATc in nuclei. |
| GO:0042130 negative regulation of T cell proliferation | ISS GO_REF:0000024 | ACCEPT | Summary: DR6 restrains CD4+ T cell proliferation: DR6-deficient CD4+ T cells hyperproliferate after TCR stimulation and antigen challenge. Reason: Core biological process, from the founding DR6 knockout study. Supporting Evidence: PMID:11485735 However, DR6(-/-) CD4(+) T cells hyperproliferated in response to TCR-mediated stimulation and protein antigen challenge. PMID:11485735 DR6, therefore, functions as a regulatory receptor for mediating CD4(+) T cell activation and maintaining proper immune responses. |
| GO:0042552 myelination | ISS GO_REF:0000024 | MODIFY | Summary: Unqualified myelination term propagated from the mouse ortholog. Reason: Correct in kind but the direction is wrong to omit: DR6 does not promote myelination, it restrains it. The evidence is that attenuating or deleting DR6 enhances myelination and remyelination. The gene already carries the correctly signed child, which should be the only myelination-related term retained. Proposed replacements: negative regulation of myelination Supporting Evidence: PMID:21725297 Attenuation of DR6 function leads to enhanced oligodendrocyte maturation, myelination and downregulation of casp3. PMID:21725297 Consistent with the DR6 antagoinst antibody studies, DR6-null mice show enhanced remyelination in both demyelination models. |
| GO:0048713 regulation of oligodendrocyte differentiation | ISS GO_REF:0000024 | ACCEPT | Summary: DR6 is expressed strongly in immature oligodendrocytes and weakly in mature ones, and restrains their differentiation. Reason: Correct and appropriately specific; the regulatory term matches the loss- and gain-of-function data. Supporting Evidence: PMID:21725297 Here we show that death receptor 6 (DR6) is a negative regulator of oligodendrocyte maturation. PMID:21725297 Attenuation of DR6 function leads to enhanced oligodendrocyte maturation, myelination and downregulation of casp3. |
| GO:0050852 T cell receptor signaling pathway | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: DR6 modulates the proliferative outcome of T cell receptor stimulation but is not itself a component of the TCR signalling cascade. Reason: Real but peripheral and arguably mis-framed. The evidence is that DR6-null CD4+ T cells respond excessively to TCR-mediated stimulation, which makes DR6 a parallel restraining receptor acting on the same cells, not a participant in the TCR pathway. The negative regulation of T cell proliferation term expresses the same observation more accurately. Supporting Evidence: PMID:11485735 However, DR6(-/-) CD4(+) T cells hyperproliferated in response to TCR-mediated stimulation and protein antigen challenge. |
| GO:0071356 cellular response to tumor necrosis factor | IDA PMID:19654028 Functional analysis of the posttranslational modifications o... | UNDECIDED | Summary: Cellular response to tumour necrosis factor, asserted as an IDA from a study of DR6 post-translational modification. Reason: Cannot be verified and should not be assumed. PMID:19654028 is a characterisation of N- and O-glycosylation, S-palmitoylation, linker-dependent surface delivery and lipid-raft partitioning of DR6; the cached record is abstract-only and describes no TNF-stimulation experiment. DR6 is moreover consistently described as an orphan receptor with no identified TNF-superfamily ligand. The curator read the full text and this review has not, so the annotation is flagged rather than removed - but it is the one row in this file whose evidence this review could not connect to its term, and it is worth a curator revisit. Supporting Evidence: PMID:19654028 In this study we document that DR6 is an extensively posttranslationally modified transmembrane protein PMID:41891813 A prior study reported that eliminating the orphan tumor necrosis factor receptor DR6 (death receptor 6, encoded by Tnfrsf21) strongly delays AxD and alters SC injury responses during WD |
| GO:0097252 oligodendrocyte apoptotic process | ISS GO_REF:0000024 | ACCEPT | Summary: DR6 overexpression in oligodendrocytes activates caspase 3 and causes cell death; attenuating DR6 downregulates caspase 3. Reason: Supported by matched gain- and loss-of-function in the ortholog, and consistent with the negative regulation of oligodendrocyte maturation that this gene also carries. Supporting Evidence: PMID:21725297 Overexpression of DR6 in oligodendrocytes leads to caspase 3 (casp3) activation and cell death. PMID:21725297 Attenuation of DR6 function leads to enhanced oligodendrocyte maturation, myelination and downregulation of casp3. |
| GO:0006915 apoptotic process | IMP PMID:22761420 Death receptor 6 induces apoptosis not through type I or typ... | KEEP AS NON CORE | Summary: Ectopically overexpressed DR6 induces apoptosis through a Bax-dependent, caspase-8- and Bid-independent mitochondrial route. Reason: Real but weak and maximally general. The phenotype depends on overexpression of a death-domain-containing receptor, which is a well-known way to force apoptosis regardless of physiological relevance, and no ligand-driven version of the experiment exists because DR6 remains an orphan receptor. The more specific, better-grounded apoptosis terms this gene carries (oligodendrocyte apoptotic process, neuron apoptotic process, B cell apoptotic process) are the informative ones. Supporting Evidence: PMID:22761420 it was found that DR6 induces apoptosis when it is overexpressed PMID:22761420 Our data demonstrated that Bax translocation is absolutely required for DR6-induced apoptosis. |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-1989771 | ACCEPT | Summary: DR6 is a type I transmembrane TNFRSF member displayed at the cell surface; plasma membrane localisation is confirmed by immunofluorescence, by mutagenesis that traps the protein intracellularly, and by orthology. Reason: Correct and well-corroborated primary location, asserted by six independent annotation routes (IBA, ISS, two IDA sources, an Ensembl-based IEA and Reactome TAS). Unaffected by any of the disputes surrounding this gene's neuronal role. Supporting Evidence: PMID:19654028 Deletion of the entire linker region between CRDs and the transmembrane domain, spanning over 130 amino acids, severely compromises the plasma membrane localization of DR6 and leads to its intracellular retention. PMID:19654028 In this study we document that DR6 is an extensively posttranslationally modified transmembrane protein |
| GO:0004888 transmembrane signaling receptor activity | ISS GO_REF:0000024 | NEW | Summary: Proposed new molecular function. GOA currently gives TNFRSF21 no molecular function beyond bare protein binding, yet DR6 is a type I plasma-membrane TNFRSF receptor with four extracellular cysteine-rich domains and a cytoplasmic death domain whose deletion in mouse consistently de-represses lymphocyte proliferation and oligodendrocyte maturation. Reason: Transmembrane signalling receptor activity is the most specific molecular function the evidence will bear. It is deliberately not the more specific GO:0005035 death receptor activity: that term requires combining with an extracellular death ligand, and DR6 remains an orphan receptor with no identified ligand, so no ligand-binding event has been demonstrated. The evidence for receptor activity is architectural and genetic rather than direct - surface display that depends on an intact juxtamembrane stalk, a functional requirement for the cytoplasmic death domain in the amyloid-beta/p75NTR pathway, and loss-of-function phenotypes in three cell types in which removing DR6 releases a brake - so ISS from the mouse ortholog is the appropriate evidence line. Proposing this term is also what keeps the review from leaving the molecular-function slot to GO:0005515, which carries no information and is here removed. Supporting Evidence: PMID:11485735 DR6, therefore, functions as a regulatory receptor for mediating CD4(+) T cell activation and maintaining proper immune responses. PMID:19654028 Deletion of the entire linker region between CRDs and the transmembrane domain, spanning over 130 amino acids, severely compromises the plasma membrane localization of DR6 and leads to its intracellular retention. PMID:23559013 Here, we demonstrate that death receptor 6 (DR6) binds to p75(NTR) and is a component of the p75(NTR) signaling complex responsible for AΞ²-induced cortical neuron death. |
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Download this section (compressed HTML)Q: What is the physiological ligand of DR6? Every function attributed to it rests on loss-of-function phenotypes or on forced overexpression; without a ligand, the molecular function can only be stated as generic transmembrane signalling receptor activity, and no death receptor activity term can be justified.
Suggested experts: TNF superfamily structural biologists, GO molecular-function curators
Q: Is APP a genuine functional ligand of DR6, or an interaction partner without receptor-ligand significance? The physical interaction is supported independently of the retracted work by a systematic extracellular interactome screen, but the mechanistic model built on it was withdrawn.
Q: Does DR6 regulate developmental axon pruning in the CNS? This is the part of the original claim that the 2026 Wallerian non-replication does not address - different process, different compartment, different trigger - and the surviving in vivo evidence comes from a single laboratory that shares authorship with the retracted paper.
Q: Should GOA record anything about DR6 and axon degeneration? At present it carries no axon-degeneration or axon-pruning term, and GO itself has no such term (only GO:0016322 neuron remodeling). The only axon-related annotation is an axonal fasciculation IEA whose rat source studied axonal degeneration instead.
Suggested experts: GO ontology developers, neuronal cell death curators
Q: What is the basis of the cellular response to tumor necrosis factor IDA from PMID:19654028? That paper characterises glycosylation, palmitoylation and raft targeting of DR6, and DR6 has no known TNF-family ligand.
Q: Are the lymphocyte and oligodendrocyte brakes the same signalling mechanism used in two cell types, or distinct pathways that converge on a shared receptor? DR6's death domain is required for the amyloid-beta neuronal pathway, but the proximal effectors in T and B cells were not identified.
Experiment: Screen a recombinant ectodomain library of the human surfaceome and secretome against multimerised DR6 ectodomain by avidity-based extracellular interaction assay, then test the top hits for the ability to reproduce DR6-dependent restraint of T cell proliferation or oligodendrocyte maturation in DR6-null versus wild-type cells.
Hypothesis: DR6 has an unidentified cell-surface ligand whose engagement transduces the growth-restraining signal.
Type: interaction screen plus functional validation
Experiment: Repeat the retinocollicular pruning analysis of PMID:24806670 in an independent laboratory, side by side in the two DR6 knockout lines used by PMID:41891813, with the Wallerian assay run on the same animals as an internal control. This tests the surviving developmental claim while holding the mouse line constant.
Hypothesis: DR6 regulates developmental CNS axon pruning independently of any role in Wallerian degeneration.
Type: independent replication
Experiment: Measure the affinity and stoichiometry of purified DR6 ectodomain against defined APP ectodomain fragments by surface plasmon resonance and mass photometry, and determine a structure of the complex. The retraction withdrew the previous interaction model, so the binding interface is currently unmapped.
Hypothesis: The DR6-APP interaction is direct and of physiological affinity.
Type: biophysics and structural biology
Experiment: Perform proximity labelling from DR6 in primary T cells, B cells and immature oligodendrocytes, and compare the interactomes; then test shared candidates by knockout for the ability to phenocopy DR6 loss in each cell type.
Hypothesis: The lymphocyte and oligodendrocyte phenotypes share a proximal intracellular effector.
Type: comparative proximity proteomics
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