CYLD is a cytoplasmic USP-family deubiquitinase that removes K63- and Met1-linked ubiquitin chains from signaling proteins. Its catalytic domain, stimulated and recruited by SPATA2, edits receptor-associated ubiquitin scaffolds and regulates inflammatory and cell-death signaling. Its N-terminal CAP-Gly region also binds microtubules and interacts with HDAC6 to inhibit tubulin deacetylation independently of ubiquitin hydrolysis. These catalytic and noncatalytic activities connect CYLD with microtubule organization, cell-cycle progression and centrosomal functions. Loss of CYLD function predisposes to cutaneous adnexal tumors.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004843 cysteine-type deubiquitinase activity | EXP PMID:27746020 The K48-K63 Branched Ubiquitin Chain Regulates NF-ΞΊB Signali... | ACCEPT | Summary: CYLD is a cysteine-dependent deubiquitinase that processes K63 chains. Reason: The complete available 27746020 abstract explicitly describes protection of K63 linkages from CYLD by K48 branching. Its full experimental text remained inaccessible, so the original EXP assay is retained with curator deference. Independent WT cleavage experiments in 32185393 and catalytic controls in 26997266/27591049 establish the enzyme activity. This does not assign K48-cleaving activity or assert complete resistance of every branched substrate. |
| GO:0004843 cysteine-type deubiquitinase activity | EXP PMID:32185393 CYLD is a causative gene for frontotemporal dementia - amyot... | ACCEPT | Summary: The disease study directly demonstrates wild-type CYLD deubiquitinase activity. Reason: Actual Methods and Figure 5 Results in 32185393 compare HEK293-purified CYLD-mycFLAG WT with inactive D681G and disease-associated M719V using K63-linked ubiquitin tetramers. WT cleavage is positive; the enhanced M719V rate is a distinct mutant result. No observable K48 cleavage was reported in that assay. Retain the catalytic-mechanism class alongside existing linkage-specific annotations. The local cache contains the abstract only; the short quotation anchors the geneβs K63 activity, while the construct and Figure 5 details come from the separately recovered original article linked in the notes. Supporting Evidence: PMID:32185393 CYLD encodes a lysine 63 deubiquitinase |
| GO:0004843 cysteine-type deubiquitinase activity | IBA GO_REF:0000033 | ACCEPT | Summary: The inferred cysteine deubiquitinase function agrees with direct human CYLD enzymology. Reason: The actual GO0004843 IBD at PTN000931062 lies on the human CYLD path, with matching 956-residue target MSA sequence and genuine mouse, fly and human experimental descendant records. The on-path losses concern ancestral ribosomal functions, not DUB activity. Human CYLD among its own donors is valid experimental grounding. Direct CYLD catalysis independently supports the inherited cysteine-DUB mechanism. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000931062 SUPPORTS TRANSFER Actual GO:0004843 IBD lies on the 23-node human target path; 956-aa MSA identity is exact. FB:FBgn0032210 SUPPORTS TRANSFER Current experimental fly CYLD descendant evidence is recovered. MGI:MGI:1921506 SUPPORTS TRANSFER Current experimental mouse Cyld descendant evidence is recovered. UniProtKB:Q9NQC7 SUPPORTS TRANSFER Human experimental evidence is legitimate self grounding of the ancestral assertion. |
| GO:0004843 cysteine-type deubiquitinase activity | IDA PMID:18313383 The structure of the CYLD USP domain explains its specificit... | ACCEPT | Summary: The structural source supports CYLDβs cysteine-dependent USP activity. Reason: The accessible original abstract establishes K63 endodeubiquitinase activity and loss of catalysis after pathogenic USP truncation. The linked 2VHF primary deposition independently identifies the human USP fragment, and subsequent directly read WT/C601A experiments establish the catalytic role. The paperβs full Methods/Results were not recovered; retain the established function with explicit curator deference rather than claiming a full-paper audit. |
| GO:0004843 cysteine-type deubiquitinase activity | IDA PMID:18636086 The tumour suppressor CYLD is a negative regulator of RIG-I-... | ACCEPT | Summary: CYLD removes ubiquitin in RIG-I antiviral signaling. Reason: The original abstract and recovered indexed Results support CYLD association with RIG-I and suppression of RIG-I/MAVS/TBK1 signaling. The curated IDA is consistent with the independently established cysteine-dependent enzyme mechanism. The cached full-text flag overstates the available main text, which contains introduction and methods but not the complete Results; the additional indexed original excerpts were assessed separately. This does not make CYLD an IKK-epsilon inhibitor. |
| GO:0004843 cysteine-type deubiquitinase activity | IDA PMID:27458237 SPATA2 promotes CYLD activity and regulates TNF-induced NF-ΞΊ... | ACCEPT | Summary: SPATA2-associated CYLD directly cleaves K63 and linear ubiquitin substrates. Reason: The recovered original DUB Results describe FLAG-CYLD purified from complemented Cyld-null MEFs and cleavage of defined K63- and M1-linked diubiquitin, enhanced by SPATA2. Catalytic-mutant controls separate cleavage from binding. Methods identify a human Addgene CYLD clone but use C598A numbering; the exact historical insert was not reconstructed, so neither official intact product is assigned solely from that numbering. Supporting Evidence: |
| GO:0004843 cysteine-type deubiquitinase activity | IDA PMID:27591049 SPATA2 Links CYLD to LUBAC, Activates CYLD, and Controls LUB... | ACCEPT | Summary: Purified CYLD USP activity is stimulated by SPATA2. Reason: The original experiments reconstitute a CYLD USPβSPATA2 complex, measure K63 and M1 chain cleavage and quantify enhanced catalytic efficiency. Sf9-derived CYLD residues 583β956 and bacterial SPATA2 fragments establish performed catalysis and activation. These shared-domain constructs do not establish equivalent activity of both intact official products. Supporting Evidence: PMID:27591049 SPATA2 binding activates CYLD-mediated hydrolysis of ubiquitin chains. |
| GO:0004843 cysteine-type deubiquitinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: The electronic catalytic annotation matches the experimentally established USP enzyme. Reason: The actual target InterPro matches IPR001394 and IPR018200 and their GO associations support a USP cysteine-type deubiquitinase. EC:3.4.19.12 remains the literal combined electronic source. Independent human CYLD enzymology and the human 583β956 USP deposition corroborate the mechanism; separate existing rows describe K63 and Met1 linkage preferences. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR001394 SUPPORTS TRANSFER Actual target membership and GO mapping agree with independently established human USP enzymology. InterPro:IPR018200 SUPPORTS TRANSFER Actual target membership and GO mapping agree with independently established human USP enzymology. EC:3.4.19.12 SUPPORTS TRANSFER Actual target membership and GO mapping agree with independently established human USP enzymology. |
| GO:0004843 cysteine-type deubiquitinase activity | TAS Reactome:R-HSA-5696627 | ACCEPT | Summary: Reactome places CYLD in the active DUB unit of a deubiquitination reaction. Reason: The actual event 5696627 points to catalyst 5696921, which names CYLD741420 as its activeUnit and places it in complex 6782801. The human reference entity is Q9NQC7, residues 1β956. This is a catalytic role, independently supported by biochemical studies, rather than a substrate-only association. |
| GO:0005515 protein binding | IPI PMID:18636086 The tumour suppressor CYLD is a negative regulator of RIG-I-... | MODIFY | Summary: The tested RIG-I partner supports a helicase-binding refinement. Reason: Two exact current MINT records join human CYLD to human O95786/RIG-I in HEK293EBNA, including tagged co-IP and endogenous anti-bait co-IP. The original indexed Results report a salt-resistant association and an antiviral regulatory context. RIG-I is a DExD/H RNA helicase; the class refinement describes the partner and does not assign RNA-helicase catalysis to CYLD or claim purified binary binding. Proposed replacements: DEAD/H-box RNA helicase binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:18636086 The tumour suppressor CYLD is a negative regulator of RIG-I-... | KEEP AS NON CORE | Summary: CYLD associates with MAVS in an antiviral signaling context. Reason: The exact human Q7Z434 pair is represented by a positive tagged co-IP in HEK293EBNA, and the recovered original Results explicitly describe MAVS association. This supports contextual binding without establishing a separate molecular adaptor activity of CYLD. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:19615732 Defining the human deubiquitinating enzyme interaction lands... | KEEP AS NON CORE | Summary: The interaction survey detects the CYLDβSPATA2 association. Reason: Two current exact-pair IntAct records from this publication describe reciprocal tagged association in HEK293T. The full screen table was not recovered, so its individual construct details are curator-deferred. Independent purified-domain and cellular experiments establish the same association and its DUB-activation context; the screen does not itself establish a new regulatory activity. |
| GO:0005515 protein binding | IPI PMID:19893491 CYLD negatively regulates cell-cycle progression by inactiva... | MODIFY | Summary: CYLD binds polymerized microtubules through its N-terminal region. Reason: The original study combines alpha-tubulin association in human cells with CYLD cosedimentation with polymerized microtubules and CAP-Gly-region analysis. The six literal MINT records include co-IP and colocalization, which are not each direct-binding assays; the separate polymer assay supports the microtubule-binding refinement. No unique TUBA1A isoform recognition is inferred from bulk-tubulin experiments. Proposed replacements: microtubule binding Supporting Evidence: PMID:19893491 CYLD associates with MTs |
| GO:0005515 protein binding | IPI PMID:19893491 CYLD negatively regulates cell-cycle progression by inactiva... | MODIFY | Summary: CYLD inhibits HDAC6-mediated tubulin deacetylation through direct interaction. Reason: The same original paper demonstrates recombinant CYLDβHDAC6 binding and inhibition of HDAC6-mediated tubulin deacetylation. The inhibition assay uses immunoprecipitated or peptide-eluted proteins with MAP-enriched bovine microtubules; it is distinct from the recombinant binding assay. CYLD residues 1β212 inhibit, and a DUB-inactive C/S construct retains the cellular tubulin-acetylation effect. These additional functional experiments support enzyme inhibitor activity while the original IPI/source fields remain literal. No inhibition of histone deacetylation or CYLD acetyltransferase activity is inferred. GO:0042826 describes the demonstrated binding to HDAC6, a histone-deacetylase-family enzyme; its partner-class label does not assert that CYLD inhibits histone deacetylation. The separately supported enzyme-inhibitor activity concerns the measured tubulin substrate. Proposed replacements: enzyme inhibitor activity histone deacetylase binding Supporting Evidence: PMID:19893491 This interaction inhibits HDAC6-mediated tubulin deacetylation |
| GO:0005515 protein binding | IPI PMID:20227366 Loss of the tumor suppressor CYLD enhances Wnt/beta-catenin ... | UNDECIDED | Summary: The exact DVL3 interaction remains source-limited. Reason: The complete available abstract establishes CYLD interaction with Dishevelled and regulation of its K63 ubiquitination, and UniProt specifically cites DVL1/DVL3 for this paper. However, the full original DVL3 construct/assay was not recovered and the current literal Q92997 pair is absent from the retrieved interaction records. Preserve the original DVL3 assertion pending verification of that precise assay; neither the empty current join nor the generic abstract disproves binding. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:22057290 The E3 ligase Itch and deubiquitinase Cyld act together to r... | MODIFY | Summary: CYLD binds the ubiquitin ligase ITCH. Reason: The full original reports co-IP and direct binding of recombinant ITCH and CYLD, dependent on the CYLD PPXY motif. ITCH supplies ubiquitin-ligase chemistry while CYLD removes K63 chains from TAK1; the ligase-binding class captures this partnership without assigning E3 activity to CYLD. No current literal pair was returned, so the positive judgment rests on the original assays. Proposed replacements: ubiquitin protein ligase binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:22057290 The E3 ligase Itch and deubiquitinase Cyld act together to r... | MODIFY | Summary: The isoform-specific ITCH assertion supports ligase binding with a product limit. Reason: The original directly establishes CYLDβITCH binding and sequential editing of TAK1 ubiquitin. The imported partner remains Q96J02-2 and its official sequence was reconstructed, but the recovered main-text construct description does not independently establish that specific ITCH product. Retain the curatorβs positive product assignment while refining its known E3-ligase class; do not claim that the paper compared ITCH isoforms. Proposed replacements: ubiquitin protein ligase binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:24981860 Human-chromatin-related protein interactions identify a deme... | KEEP AS NON CORE | Summary: Affinity purification supports a CYLDβSPATA2 association. Reason: The exact positive IntAct pair from PMID24981860 records tandem affinity purification in human HEK293 cells. This is an association assay, not proof that CYLD is a chromatin enzyme. The full original target table was not recovered; independent biochemical CYLDβSPATA2 work corroborates the pair and supplies the functional context. |
| GO:0005515 protein binding | IPI PMID:25134987 The deubiquitinating enzyme CYLD controls apical docking of ... | KEEP AS NON CORE | Summary: CYLD associates with the centrosomal protein CEP350/CAP350. Reason: The recovered original identifies CAP350 by affinity purification and mass spectrometry and validates reciprocal association with CYLD in human cells. Domain-mapping co-IP supports recruitment of CYLD to centrosomes; it does not demonstrate a purified binary interaction or an intrinsic motor activity. The absent current literal interaction record does not negate these original results. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:26997266 CYLD Limits Lys63- and Met1-Linked Ubiquitin at Receptor Com... | KEEP AS NON CORE | Summary: CYLD associates with RNF31/HOIP through the SPATA2-containing complex. Reason: The curated RNF31 pair is compatible with the receptor-complex association in the original source. Later purified-component studies show that SPATA2 bridges CYLD to HOIP and fail to detect direct CYLDβHOIP binding under their tested conditions. Retain the contextual complex association, without refining it into a direct ligase-binding interface or substituting SPATA2 for the imported partner. |
| GO:0005515 protein binding | IPI PMID:27307491 SPATA2 links CYLD to the TNF-Ξ± receptor signaling complex an... | KEEP AS NON CORE | Summary: SPATA2 links CYLD to TNF receptor signaling complexes. Reason: The full source identifies the CYLDβSPATA2 association by human-cell proteomics and maps the SPATA2 N-terminal PUB region to the CYLD USP domain. SPATA2 depletion prevents CYLD recruitment. This supports the pair while keeping recruitment/adaptor activity assigned to SPATA2 rather than inferring it for CYLD merely from association. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:27458237 SPATA2 promotes CYLD activity and regulates TNF-induced NF-ΞΊ... | KEEP AS NON CORE | Summary: CYLD binds its activator SPATA2. Reason: Recovered original Results show co-purification of SPATA2 with wild-type and catalytic-mutant FLAG-CYLD and increased cleavage of defined ubiquitin substrates. Binding is retained independently of catalytic competence. The C598A versus official C601 numbering discrepancy is unresolved at exact clone-sequence level and is not treated as evidence for a particular official product. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:27545878 SPATA2-Mediated Binding of CYLD to HOIP Enables CYLD Recruit... | KEEP AS NON CORE | Summary: SPATA2 directly connects CYLD with HOIP-containing complexes. Reason: The original interaction and domain experiments establish SPATA2βCYLD binding, while purified HOIP PUB and CYLD USP do not directly associate in the tested assays. SPATA2 bridges this gap and permits receptor-complex recruitment. The CYLDβSPATA2 interaction is positive; a separate CYLD adaptor function is not demonstrated. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:27591049 SPATA2 Links CYLD to LUBAC, Activates CYLD, and Controls LUB... | KEEP AS NON CORE | Summary: A reconstituted CYLDβSPATA2 complex supports the specific association. Reason: The original reconstitutes CYLD USP 583β956 with SPATA2 PUB 1β241, maps an interface near CYLD Leu622 and demonstrates DUB activation. CYLD B-box dimerization permits a 2:2 arrangement; the isolated B-box is not itself sufficient for SPATA2 binding. These fragment data support the interaction without specifying which intact CYLD splice product was present. Supporting Evidence: |
| GO:0005737 cytoplasm | EXP PMID:18313383 The structure of the CYLD USP domain explains its specificit... | ACCEPT | Summary: Cytoplasmic localization is compatible with established CYLD biology. Reason: The 18313383 abstract explicitly connects its B-box to subcellular localization, but the original localization panel was not recovered. Retain this established gene-level location with curator deference, supported independently by actual cytoplasmic CYLD staining described in 32185393 and its cytoplasmic signaling contexts. Do not silently narrow the original multipool cytoplasm assertion to cytosol. |
| GO:0005737 cytoplasm | EXP PMID:32185393 CYLD is a causative gene for frontotemporal dementia - amyot... | ACCEPT | Summary: The cited study directly reports cytoplasmic CYLD staining. Reason: The actual neuropathology Results and Figure 2 caption report CYLD in balloon-neuron cytoplasm in all examined cases and diffuse neuronal cytoplasmic staining in the familial cases. These are endogenous staining observations in disease tissue, distinct from the paperβs TDP-43 redistribution experiments and transfected mouse neurons. The broad location does not imply disease-mutant findings are normal physiological mechanisms. Supporting Evidence: |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: The UniProt location mapping correctly captures cytoplasmic CYLD. Reason: The literal Swiss-Prot subcellular-location statement maps to cytoplasm and is supported by the source-specific human localization and interaction studies. Cytoplasmic localization is compatible with regulated centrosomal, microtubule and receptor-associated pools; this broad term does not require exclusive residence. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0086 SUPPORTS TRANSFER Literal cytoplasm mapping; human cellular and biochemical observations corroborate it. |
| GO:0005813 centrosome | IDA PMID:25134987 The deubiquitinating enzyme CYLD controls apical docking of ... | ACCEPT | Summary: Human CYLD localizes to centrosomes. Reason: The recovered original detects endogenous CYLD at centrosomes in human RPE1 cells, validates centrosomal enrichment and analyzes CAP350-dependent recruitment. This supports the specific organelle location, without requiring every endogenous CYLD molecule to be centrosomal. The local abstract quotation anchors localization; human RPE1 and CAP350 assay details derive from the separately recovered original publisher PDF. Supporting Evidence: PMID:25134987 CYLD localizes at centrosomes and basal bodies |
| GO:0005813 centrosome | IEA GO_REF:0000044 | ACCEPT | Summary: The centrosomal electronic mapping is experimentally corroborated. Reason: The Swiss-Prot centrosome statement cites PMID25134987, whose actual human-cell localization and recruitment experiments were read. The mapping therefore retains a supported location rather than predicting it solely from a domain name. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0048 SUPPORTS TRANSFER Literal centrosome mapping, grounded in the recovered human RPE1 study. Supporting Evidence: |
| GO:0005819 spindle | IDA PMID:25134987 The deubiquitinating enzyme CYLD controls apical docking of ... | ACCEPT | Summary: CYLD is detected along the mitotic spindle. Reason: The original human-cell experiments report centrosomal and spindle localization in metaphase. Preserve that stage-specific location. The same source did not observe central-spindle or midbody staining under its conditions, which does not invalidate the separate midbody experiment in PMID17495026. Supporting Evidence: |
| GO:0005819 spindle | IEA GO_REF:0000044 | ACCEPT | Summary: The spindle mapping follows a supported UniProt location statement. Reason: The electronic source is the Swiss-Prot spindle annotation grounded in PMID25134987. Human mitotic-cell staining supports this location; it is not an inference that CYLD supplies spindle motor activity. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0251 SUPPORTS TRANSFER Literal spindle mapping; metaphase staining supports the location. Supporting Evidence: |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: The cytosolic IBA is supported by the actual ancestral placement and human evidence. Reason: The 956-residue human MSA sequence maps to PTN002483694 in the 510-node tree. The cytosol IBD is at on-path root PTN000216320, with current experimental grounding including human CYLD and ribosomal-family descendants. The pathway IRD losses concern translation/ribosome functions, not this broad cytosol term. Mixed family membership does not refute the supported ancestral location or the human evidence. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000216320 SUPPORTS TRANSFER Root cytosol IBD is on the actual target path. On-path IRD losses concern ribosomal functions, not cytosol. UniProtKB:Q9NQC7 SUPPORTS TRANSFER Current human experimental cytosol annotation supports the location and legitimate self grounding. PomBase:SPAC22H12.04c SUPPORTS TRANSFER Current O94438 HDA cytosol record cites PMID:16823372. MGI:MGI:1202063 SUPPORTS TRANSFER Current P97351 IDA cytosol record cites PMID:10713066; this is a ribosomal descendant, not a CYLD ortholog. UniProtKB:P61247 SUPPORTS TRANSFER Current human ribosomal-protein cytosol evidence is part of the broadly placed IBD; it is not asserted to be a CYLD homolog with DUB activity. FB:FBgn0017545 UNRESOLVED This historical donor remains literal; a current same-term experimental record was not recovered. RGD:62078 UNRESOLVED This historical donor remains literal; a current same-term experimental record was not recovered. Supporting Evidence: |
| GO:0005829 cytosol | IDA PMID:18313383 The structure of the CYLD USP domain explains its specificit... | ACCEPT | Summary: A cytosolic pool of CYLD supports its intracellular deubiquitinase function. Reason: Retain the original IDA with curator deference for established cytosolic CYLD. The 18313383 full localization assay was not recovered and is not claimed independently inspected. Cytoplasmic receptor-proximal chain editing and recruitment in the directly read 26997266/27591049 studies provide compatible functional context without proving exclusive cytosolic localization. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5357831 | ACCEPT | Summary: CYLD is cytosolic in its phosphorylation reaction. Reason: Event 5357831 contains unmodified CYLD741420 as input and pS418-CYLD5212667 as output, both Q9NQC7 residues 1β956 in cytosol. CHUK/IKBKB perform the phosphorylation; CYLD is the substrate. The localization is supported without transferring kinase activity to CYLD. Supporting Evidence: Reactome:R-HSA-5357831 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5357845 | ACCEPT | Summary: The RIPK1 deubiquitination model contains cytosolic CYLD. Reason: Event 5357845 points to catalyst 5357880 and member set5357750 containing CYLD741420; phosphorylated CYLD5212667 is also modeled as a regulator. Both target forms are cytosolic. The model distinguishes a DUB role from regulation of the DUB by phosphorylation. Supporting Evidence: Reactome:R-HSA-5357845 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5357928 | ACCEPT | Summary: CYLD is a cytosolic participant recruited by CLIP3. Reason: Event 5357928 contains CYLD741420 as input and as a component of output complex 5357950. The target entity is explicitly cytosolic. Recruitment to a receptor-associated complex does not make CYLD a transmembrane protein. Supporting Evidence: Reactome:R-HSA-5357928 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5696627 | ACCEPT | Summary: The catalytic CYLD entity is explicitly cytosolic. Reason: The actual catalyst 5696921 names CYLD741420 as activeUnit in event 5696627, and the target is a cytosolic Q9NQC7 entity. This location is consistent with independently demonstrated cytoplasmic DUB activity. Supporting Evidence: Reactome:R-HSA-5696627 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-741411 | ACCEPT | Summary: Cytosolic CYLD is the modeled NEMO deubiquitinase. Reason: Event 741411 points through catalyst 741421 to CYLD741420, whose compartment is cytosol. The event models removal of regulatory ubiquitin from NEMO, not NEMO catalytic activity. Supporting Evidence: Reactome:R-HSA-741411 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-936390 | ACCEPT | Summary: The RIG-I event explicitly uses cytosolic CYLD. Reason: Event 936390 points through catalyst 741421 to human CYLD741420 in cytosol. Its summary incorrectly calls CYLD an OTU-domain DUB; official sequence and structural evidence place CYLD in the USP/C19 family. That family-description error does not invalidate the target identity or cytosolic DUB role. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9793680 | ACCEPT | Summary: CYLD is present in the modeled cytosolic part of an OPTN-associated TNFR complex. Reason: The actual path 9793680β9793686β9817363β9796690 reaches CYLD741420. The latter is explicitly cytosolic even though the assembled receptor complex also includes a membrane receptor. This supports the location, not assignment of OPTN ubiquitin-binding activity to CYLD. Supporting Evidence: Reactome:R-HSA-9793680 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9796379 | ACCEPT | Summary: SPATA2βLUBAC recruitment includes cytosolic CYLD. Reason: Both input complex 9796690 and the output TNFR complex of event 9796379 contain CYLD741420 in cytosol. The association is independently supported by human-cell and purified-component studies; CYLD is the associated DUB rather than the LUBAC E3 catalytic subunit. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9796691 | ACCEPT | Summary: CYLD is the cytosolic DUB component linked to LUBAC by SPATA2. Reason: Event 9796691 contains CYLD741420 as input and in complex 9796690 as output. Its human reference and cytosolic compartment are explicit. SPATA2 supplies the bridging interaction; no direct CYLDβHOIP contact is inferred. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9815507 | ACCEPT | Summary: Cytosolic CYLD is a substrate of MIB2-mediated ubiquitination. Reason: The actual event 9815507 follows CYLD in complex 9816107 to K48-polyubiquitinated target 9818664, both cytosolic. MIB2 supplies the ligase chemistry and CYLD is its substrate. The location is valid without assigning protein ubiquitination as a performed CYLD process. Supporting Evidence: Reactome:R-HSA-9815507 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9815510 | ACCEPT | Summary: The MIB2-binding event contains cytosolic CYLD. Reason: Event 9815510 links input CYLD741420 to output complex 9816107, with the same cytosolic human target identity. The source summarizes cellular interaction and colocalization experiments; this annotation concerns localization rather than a new ligase role. Supporting Evidence: Reactome:R-HSA-9815510 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9817362 | ACCEPT | Summary: CYLD remains cytosolic while associated LUBAC modifies RIPK1. Reason: The actual event 9817362 includes CYLD741420 within 9796690 in substrate/catalyst complexes and as an active unit in regulation. LUBAC performs the linear ubiquitination of RIPK1; CYLD supplies opposing DUB activity. The cytosolic localization is supported without conflating these chemistries. Supporting Evidence: Reactome:R-HSA-9817362 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9817397 | ACCEPT | Summary: The kinase reaction includes a cytosolic CYLD-containing assembly. Reason: Event 9817397 reaches CYLD741420 through TNFR complex 9817409 and the SPATA2βCYLDβLUBAC component9796690. TBK1/IKBKE phosphorylate RIPK1 in this event; CYLD complex membership supports its cytosolic location, not kinase activity. Supporting Evidence: Reactome:R-HSA-9817397 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9817400 | ACCEPT | Summary: CYLD acts on RIPK1 ubiquitin chains from the cytosolic receptor complex. Reason: Event 9817400 contains CYLD741420 in its input complex and names it as activeUnit of catalyst 9818831. This is a specific cytosolic K63-deubiquitination role supported by the model and independent CYLD enzymology. Supporting Evidence: Reactome:R-HSA-9817400 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9817411 | ACCEPT | Summary: The modeled kinase-recruitment complex includes cytosolic CYLD. Reason: Event 9817411 contains CYLD741420 through component9796690 in both the input and output TNFR assemblies. This supports localization while TBK1/IKBKE recruitment and kinase functions remain attributed to those proteins. Supporting Evidence: Reactome:R-HSA-9817411 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9818789 | ACCEPT | Summary: Cytosolic CYLD is present in the modeled RIPK1 phosphorylation assembly. Reason: The path 9818789β9818787β9817363β9796690β741420 establishes target membership. CHUK/IKBKB phosphorylate RIPK1; the CYLD assertion is the cytosolic location and does not depend on assigning that catalytic reaction to CYLD. Supporting Evidence: Reactome:R-HSA-9818789 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9818975 | ACCEPT | Summary: The linear-chain cleavage event specifies cytosolic CYLD. Reason: Event 9818975 names CYLD741420 as activeUnit of catalyst 9818830 and includes it in complex 9817363. The entity has the explicit cytosol compartment and human Q9NQC7 reference. Its M1-hydrolase role is independently supported. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9824874 | ACCEPT | Summary: OPTN-mediated recruitment places CYLD in a cytosolic signaling assembly. Reason: Event 9824874 includes free CYLD741420 and CYLD within output complex 9824875. The target remains cytosolic. The model summarizes recruitment to the TNFR complex; it does not establish constitutive membrane insertion or an OPTN-like autophagy-receptor activity in CYLD. Supporting Evidence: Reactome:R-HSA-9824874 |
| GO:0005856 cytoskeleton | IEA GO_REF:0000044 | TOO GENERAL | Summary: The supported cytoskeleton mapping is entailed by more specific accepted locations. Reason: The Swiss-Prot cytoskeleton mapping agrees with human-cell staining and biochemical microtubule association. Accepted cytoplasmic microtubule and centrosome annotations already entail cytoskeleton through GO ancestry. TOO_GENERAL therefore records redundant specificity, without questioning the source mapping or inferring actin binding. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0090 SUPPORTS TRANSFER Literal cytoskeleton mapping, corroborated by microtubule association. |
| GO:0005881 cytoplasmic microtubule | IDA PMID:17495026 The tumor suppressor CYLD regulates entry into mitosis. | ACCEPT | Summary: CYLD associates with cytoplasmic microtubules. Reason: The original human-cell study detects CYLD along microtubules, and independent cosedimentation and CAP-Gly mapping directly support this association. Localization is retained separately from the molecular binding refinement. |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: A peripheral plasma-membrane-associated pool is plausible and curated. Reason: The literal UniProt mapping describes a peripheral protein on the cytoplasmic side, consistent with stimulus-dependent recruitment of CYLD to TNFR signaling complexes. Retain this contextual broad membrane location without calling CYLD an integral membrane protein or claiming that the precise leaflet assay from PMID20194890 was fully verified. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB-SubCell:SL-0039 SUPPORTS TRANSFER Official peripheral membrane-associated pool; not integral insertion or a separately verified leaflet assay. |
| GO:0007346 regulation of mitotic cell cycle | IBA GO_REF:0000033 | ACCEPT | Summary: CYLD contributes to regulation of mitotic progression. Reason: The GO0007346 IBD at PTN002625528 is on the exact human target path and is grounded in human CYLD IMP evidence from PMID17495026. Human CYLD in its own source list is legitimate experimental grounding. The original siRNA/rescue and microtubule/HDAC6 work support a regulatory role, not cyclin-dependent kinase catalysis. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002625528 SUPPORTS TRANSFER Actual on-path GO:0007346 IBD is grounded by human CYLD IMP PMID:17495026; self evidence is valid. UniProtKB:Q9NQC7 SUPPORTS TRANSFER Actual on-path GO:0007346 IBD is grounded by human CYLD IMP PMID:17495026; self evidence is valid. |
| GO:0007346 regulation of mitotic cell cycle | IMP PMID:17495026 The tumor suppressor CYLD regulates entry into mitosis. | ACCEPT | Summary: Human CYLD perturbation alters entry into mitosis. Reason: CYLD depletion delays the G2/M transition in human cells, with rescue by wild-type but not the tested catalytic mutant. PLK1 association and NF-kappaB controls delimit the mechanism; the experiment does not establish PLK1 as a directly deubiquitinated substrate. Other CYLD/HDAC6 contexts can slow cell-cycle progression, so the broad regulation term appropriately avoids a universal direction. Supporting Evidence: PMID:17495026 CYLD is also required for timely entry into mitosis |
| GO:0008270 zinc ion binding | IDA PMID:18313383 The structure of the CYLD USP domain explains its specificit... | KEEP AS NON CORE | Summary: CYLD binds structural zinc in the USP-inserted B-box. Reason: The original abstract identifies the zinc-binding B-box. Independent examination of primary deposition 2VHF confirms a human USP fragment with bound zinc and explicit Cys/His metal contacts; current UniProt maps the corresponding sites. This is a structural feature of the enzyme and its interaction module, not evidence that zinc catalyses ubiquitin hydrolysis or a separate principal molecular activity. Supporting Evidence: |
| GO:0009898 cytoplasmic side of plasma membrane | IDA PMID:20194890 CYLD regulates angiogenesis by mediating vascular endothelia... | UNDECIDED | Summary: The precise plasma-membrane leaflet assignment needs the original localization result. Reason: The recovered original Figure 2 caption in PMID20194890 specifies CYLD immunoblots of HUVEC membrane, lysate and medium fractions, and the Methods specify plasma-membrane extraction. The actual fraction result and a leaflet-resolving experiment were not independently inspected. Preserve the positive IDA while leaving this precise compartment undecided; the studyβs migration phenotype and the caption alone do not establish the inner-leaflet conclusion. Supporting Evidence: |
| GO:0010803 regulation of tumor necrosis factor-mediated signaling pathway | IDA PMID:26997266 CYLD Limits Lys63- and Met1-Linked Ubiquitin at Receptor Com... | KEEP AS NON CORE | Summary: CYLD modulates TNF signaling in receptor-associated contexts. Reason: The original source links CYLD catalytic activity to receptor-complex ubiquitination and inflammatory signaling. TNF responses vary by cell system and pathway readout; the broad existing regulatory process is retained as contextual rather than promoted to an additional core activity. |
| GO:0010803 regulation of tumor necrosis factor-mediated signaling pathway | IDA PMID:27458237 SPATA2 promotes CYLD activity and regulates TNF-induced NF-ΞΊ... | KEEP AS NON CORE | Summary: SPATA2-dependent recruitment and activation connect CYLD with TNF responses. Reason: The recovered original Results show SPATA2-dependent CYLD recruitment and DUB activation, with altered TNF-induced NF-kappaB/MAPK and death responses. Distinguish the CYLD biochemical experiments from SPATA2-null cell phenotypes and retain the broad regulatory assertion with that boundary. Supporting Evidence: |
| GO:0010803 regulation of tumor necrosis factor-mediated signaling pathway | IDA PMID:27591049 SPATA2 Links CYLD to LUBAC, Activates CYLD, and Controls LUB... | KEEP AS NON CORE | Summary: The CYLDβSPATA2 system modulates TNF receptor signaling contextually. Reason: The source directly reconstitutes DUB activation and examines human U2OS cellular responses. NOD2 effects are stronger than TNF NF-kappaB effects in that system, so this is not a claim that CYLD uniformly suppresses every TNF output. The contextual TNF-regulation assertion remains reasonable. Supporting Evidence: |
| GO:0010803 regulation of tumor necrosis factor-mediated signaling pathway | TAS Reactome:R-HSA-5357905 | KEEP AS NON CORE | Summary: The curated pathway places CYLD at TNFR1 ubiquitin checkpoints. Reason: The actual pathway 5357905 reaches CYLD in recruited complexes and in K63/M1-deubiquitination reactions. This is an experimentally grounded regulatory role; it does not imply that CYLD performs LUBAC ubiquitination, kinase phosphorylation or caspase chemistry also present in the pathway. Supporting Evidence: Reactome:R-HSA-5357905 |
| GO:0016579 protein deubiquitination | IDA PMID:29291351 The deubiquitinating enzyme cylindromatosis mitigates nonalc... | ACCEPT | Summary: CYLD deubiquitinates a signaling substrate in hepatic inflammatory models. Reason: The original shows CYLD association with TAK1 and catalytic-domain-dependent reduction of K63 ubiquitination, alongside mouse liver and human-labelled L02 cellular experiments. The separate in-vitro ubiquitination section concerns TRIM47 modifying CYLD. Retain the broad deubiquitination process without misdescribing that section as a purified CYLDβTAK1 reaction. Supporting Evidence: |
| GO:0016579 protein deubiquitination | IEA GO_REF:0000002 | ACCEPT | Summary: The actual InterPro association supports the DUB process. Reason: The target contains IPR001394, whose current mapping includes protein deubiquitination. Human biochemical and cellular evidence independently establishes the performed ubiquitin-cleavage step. The mapping is not being accepted merely because CYLD is required for an unrelated phenotype. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR001394 SUPPORTS TRANSFER Actual target family match and current protein-deubiquitination mapping are biochemically corroborated. |
| GO:0016579 protein deubiquitination | TAS Reactome:R-HSA-5688426 | ACCEPT | Summary: CYLD performs deubiquitination in the curated pathway. Reason: The actual selected path 5688426β5689880β5696627 leads to a catalyst with CYLD activeUnit 741420. This is performed chain removal, distinct from the events in which CYLD is ubiquitinated as another enzymeβs substrate. Supporting Evidence: Reactome:R-HSA-5688426 Reactome:R-HSA-5696627 |
| GO:0019901 protein kinase binding | IPI PMID:17495026 The tumor suppressor CYLD regulates entry into mitosis. | KEEP AS NON CORE | Summary: CYLD associates with PLK1 in a mitotic context. Reason: The original human-cell study identifies PLK1 by crosslinked co-IP/mass spectrometry and validates the association. The partner is an established protein kinase, so the specific binding class is supported despite an empty current literal interaction join. Direct PLK1 deubiquitination remains a hypothesis in this source. Supporting Evidence: |
| GO:0019901 protein kinase binding | IPI PMID:18636086 The tumour suppressor CYLD is a negative regulator of RIG-I-... | KEEP AS NON CORE | Summary: CYLD associates with IKK-epsilon without uniformly inhibiting its signaling output. Reason: The exact human Q14164 pair records tagged co-IP in HEK293EBNA and is described in the recovered original Results. Its salt-sensitive association supports the kinase-binding class, but the reporter experiments distinguish IKK-epsilon from TBK1 and do not support claiming universal inhibition of the bound kinases. Supporting Evidence: |
| GO:0019901 protein kinase binding | IPI PMID:18636086 The tumour suppressor CYLD is a negative regulator of RIG-I-... | KEEP AS NON CORE | Summary: CYLD associates with TBK1 in the antiviral signaling assay. Reason: The exact human Q9UHD2 pair is a positive tagged co-IP in HEK293EBNA, with a salt-sensitive association in the original Results. This supports contextual protein-kinase binding; reporter inhibition is not by itself a purified substrate-deubiquitination assay. Supporting Evidence: |
| GO:0030496 midbody | IDA PMID:17495026 The tumor suppressor CYLD regulates entry into mitosis. | KEEP AS NON CORE | Summary: CYLD is detected at the midbody in the original human-cell experiment. Reason: PMID17495026 reports tagged CYLD localization at the midbody during cytokinesis. A later centrosome study did not observe that signal under its conditions. Retain the actual source-specific location without converting differing cell/construct conditions into a universal contradiction. |
| GO:0032480 negative regulation of type I interferon production | TAS Reactome:R-HSA-936440 | KEEP AS NON CORE | Summary: RIG-I deubiquitination can limit type-I interferon production. Reason: The actual pathway 936440β936390β741421β741420 assigns CYLD a DUB role in the RIG-I pathway. The original antiviral study reports suppression of RIG-I/MAVS/TBK1 signaling. This supports a contextual regulatory output, not an interferon biosynthetic or receptor activity. |
| GO:0034451 centriolar satellite | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: HPA immunofluorescence supports a centriolar-satellite location. Reason: The actual HPA050095 immunocytochemistry records report centriolar-satellite staining in A431, HEK293, U2OS and other profiled human cell lines, with additional basal-body/transition-zone signals in selected ciliated conditions. These antibody-level records support the existing location; image pixels were not independently reviewed and the observation does not distinguish the two official CYLD products. Supporting Evidence: GO_REF:0000052 |
| GO:0035872 nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway | TAS Reactome:R-HSA-168638 | KEEP AS NON CORE | Summary: CYLD participates in NOD receptor signaling through ubiquitin removal. Reason: The actual pathway 168638β741411 uses CYLD as the NEMO deubiquitinase, and independent NOD2 studies directly connect CYLD catalysis with RIPK2 ubiquitination and downstream responses. This is performed regulatory work in the pathway, not merely expression after stimulation. Its context is kept separate from the general catalytic core. |
| GO:0036064 ciliary basal body | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: The basal-body transfer is grounded in a genuine mouse localization experiment. Reason: The exact Q80TQ2 donor IDA for GO0036064 cites PMID25134987. Its original mouse ependymal-cell data show basal-body localization, alongside human RPE1 centrosomal and ciliogenesis evidence. Retain the conserved location as non-core; the mouse image is not relabeled as a direct human assay. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q80TQ2 SUPPORTS TRANSFER Literal current mouse same-term GO:0036064 experimental donor cites PMID:25134987. Mouse ependymal basal-body localization is not relabeled as a human IDA. Supporting Evidence: |
| GO:0043124 negative regulation of canonical NF-kappaB signal transduction | IDA PMID:27746020 The K48-K63 Branched Ubiquitin Chain Regulates NF-ΞΊB Signali... | ACCEPT | Summary: CYLD limits canonical inflammatory NF-kappaB signaling through ubiquitin-chain removal. Reason: The 27746020 abstract describes K48 branching protecting K63 chains from CYLD and amplifying IL-1beta-associated NF-kappaB signaling; its full assay was not recovered. Retain the established canonical regulatory function with curator deference, independently supported by actual CYLD WT/catalytic-mutant, RelA, I-kappaB and reporter experiments in 26997266 and 32185393. Effects differ across receptor and cell conditions; this is not universal suppression of every TNF endpoint. |
| GO:0043226 organelle | IEA GO_REF:0000117 | TOO GENERAL | Summary: The supported organelle assertion is entailed by more specific accepted locations. Reason: Among 3142 alternative ARBA branches, zero-based branch 1117 matches the targetβs three CATH FunFam signatures; no unknown predicate was assumed true. The broad organelle output is biologically compatible with CYLD. Accepted centrosome and cytoplasmic microtubule locations already entail it through their GO ancestry, so TOO_GENERAL records redundancy rather than a failed transfer or a false location. It does not specify a membrane-bounded organelle. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: ARBA:ARBA00029065 SUPPORTS TRANSFER Only zero-based branch 1117 of 3142 matches all three literal CATH FunFam predicates. Organelle is broad but compatible with the cytoskeletal/centrosomal evidence. Supporting Evidence: |
| GO:0045087 innate immune response | IDA PMID:26997266 CYLD Limits Lys63- and Met1-Linked Ubiquitin at Receptor Com... | KEEP AS NON CORE | Summary: CYLD regulates innate receptor responses through direct ubiquitin editing. Reason: The original NOD2 and receptor-complex work demonstrates CYLD-dependent removal of signaling ubiquitin and altered downstream inflammatory output. This supports contextual involvement in innate immune responses. CYLD is not inferred to recognize pathogen ligands itself. Supporting Evidence: |
| GO:0046329 negative regulation of JNK cascade | IDA PMID:29291351 The deubiquitinating enzyme cylindromatosis mitigates nonalc... | KEEP AS NON CORE | Summary: CYLD limits TAK1-dependent JNK signaling in the tested hepatic context. Reason: The original combines hepatic Cyld perturbation, TAK1 association/K63-ubiquitination analysis and JNK readouts. Human-labelled L02 experiments and mouse liver disease models are distinct. The negative-regulation assertion is supported without claiming a direct JNK catalytic substrate. Supporting Evidence: |
| GO:0048471 perinuclear region of cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: The perinuclear mapping is retained as a contextual location. Reason: The literal Swiss-Prot statement includes the perinuclear region of cytoplasm, and centrosomal/cytoplasmic localization is experimentally established. Retain the curated broad spatial description without treating perinuclear cytoplasm as nuclear-envelope lumen or asserting exclusive residence. Its exact supporting image was not separately resolved. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB-SubCell:SL-0198 SUPPORTS TRANSFER Literal perinuclear-cytoplasm statement; not a nuclear-envelope-lumen claim. Supporting Evidence: |
| GO:0050727 regulation of inflammatory response | IDA PMID:27591049 SPATA2 Links CYLD to LUBAC, Activates CYLD, and Controls LUB... | KEEP AS NON CORE | Summary: CYLDβSPATA2 activity regulates inflammatory signaling. Reason: The source directly establishes DUB activation and increased NOD2-driven RIPK2 ubiquitination, NF-kappaB activation and IL-8 output after CYLD or SPATA2 loss. TNF effects differ in the same cells. Retain this contextual inflammatory-regulation process rather than a uniform anti-inflammatory action in every tissue. Supporting Evidence: |
| GO:0050728 negative regulation of inflammatory response | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: A mouse intestinal study supports conserved negative regulation of inflammation. Reason: The exact Q80TQ2 donor IMP cites PMID32424362. Mouse Cyld loss enhances NLRP6βASC assembly, caspase activation and colonic inflammation; catalytic rescue and genetic/antibody IL-18 tests provide mechanistic grounding. Human tissue findings are correlative, so this remains an orthology-supported contextual assertion, not a direct human colitis intervention. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q80TQ2 SUPPORTS TRANSFER Literal current mouse same-term GO:0050728 experimental donor cites PMID:32424362. Mouse intestinal perturbation and catalytic rescue; human tissue findings are correlative. Supporting Evidence: |
| GO:0060544 regulation of necroptotic process | IDA PMID:27458237 SPATA2 promotes CYLD activity and regulates TNF-induced NF-ΞΊ... | UNDECIDED | Summary: The precise source-specific necroptosis assay is not resolved. Reason: Recovered indexed original text from PMID27458237 shows CYLDβSPATA2 DUB activation and SPATA2-dependent complex-II/caspase/apoptosis experiments, while discussing earlier CYLD necroptosis studies. The full original and supplements were not inspected sufficiently to locate the exact CYLD necroptosis IDA underlying this row. Preserve it undecided rather than rejecting it from the abstract or substituting a different paperβs mouse experiment. |
| GO:0061578 K63-linked deubiquitinase activity | EXP PMID:26997266 CYLD Limits Lys63- and Met1-Linked Ubiquitin at Receptor Com... | ACCEPT | Summary: CYLD edits K63 ubiquitin linkages at signaling complexes. Reason: The actual 26997266 Results distinguish CYLD WT from C601A and show increased K63/M1-modified RIPK2 after CYLD depletion. Linkage-selective UbiCRest resolves both linkage classes; the main text also explicitly points to direct in-vitro CYLD cleavage in Figure S1B. That supplementary panel was not separately inspected. Independently read purified-domain assays in 27591049 confirm K63 hydrolysis. |
| GO:0061578 K63-linked deubiquitinase activity | IBA GO_REF:0000033 | ACCEPT | Summary: The inferred K63 deubiquitinase activity agrees with direct human CYLD assays. Reason: The actual K63-deubiquitinase IBD at PTN000931062 lies on the target path and is grounded in genuine experimental descendants, including human CYLD. The current IBD additionally lists a zebrafish donor; the original imported WITH/FROM remains unchanged. Direct human/construct biochemical evidence supports K63 cleavage without imposing a donor-count requirement. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000931062 SUPPORTS TRANSFER Actual on-path PTN000931062 IBD has current experimental descendant support; the original donor list remains literal, including legitimate human self evidence. FB:FBgn0032210 SUPPORTS TRANSFER Actual on-path PTN000931062 IBD has current experimental descendant support; the original donor list remains literal, including legitimate human self evidence. MGI:MGI:1921506 SUPPORTS TRANSFER Actual on-path PTN000931062 IBD has current experimental descendant support; the original donor list remains literal, including legitimate human self evidence. UniProtKB:Q9NQC7 SUPPORTS TRANSFER Actual on-path PTN000931062 IBD has current experimental descendant support; the original donor list remains literal, including legitimate human self evidence. |
| GO:0061578 K63-linked deubiquitinase activity | IDA PMID:18313383 The structure of the CYLD USP domain explains its specificit... | ACCEPT | Summary: The structural study reports K63-chain endodeubiquitinase activity. Reason: The full available 18313383 abstract explicitly reports K63 endodeubiquitinase activity and structure-dependent specificity. Full original assay details remain unavailable. The curated IDA is retained with that access limit and independent K63 cleavage corroboration from 32185393/27591049; the RCSB deposition is structural corroboration, not a substitute for reading an enzyme assay. |
| GO:0061578 K63-linked deubiquitinase activity | IDA PMID:26997266 CYLD Limits Lys63- and Met1-Linked Ubiquitin at Receptor Com... | ACCEPT | Summary: The K63-specific assertion is supported in the cited signaling study. Reason: The exact IDA tuple is distinct from the EXP tuple and remains intact. Actual 26997266 Results show catalytic dependence and linkage-resolved K63/M1 remodeling of RIPK2, with direct CYLD chain cleavage cited in its supplementary Figure S1B; that panel was not independently viewed. Directly read 27591049 purified-domain experiments provide independent K63 activity support. |
| GO:0061578 K63-linked deubiquitinase activity | IDA PMID:27746020 The K48-K63 Branched Ubiquitin Chain Regulates NF-ΞΊB Signali... | ACCEPT | Summary: K48 branching modulates access to the K63 bonds cleaved by CYLD. Reason: The complete available 27746020 abstract positively identifies CYLD-mediated K63 deubiquitination and reports protection by K48 branches. Full original assay access failed, so exact substrate construction and assay conditions are not claimed verified. Independent human WT K63 cleavage supports retaining the curated positive; branching is not evidence for K48 hydrolysis by CYLD. Supporting Evidence: PMID:27746020 protects K63 linkages from CYLD-mediated deubiquitylation |
| GO:0061578 K63-linked deubiquitinase activity | IDA PMID:29291351 The deubiquitinating enzyme cylindromatosis mitigates nonalc... | ACCEPT | Summary: The hepatic study supports removal of K63 chains by CYLD. Reason: The original reports CYLD-dependent loss of K63 ubiquitination on TAK1 with catalytic-domain controls and downstream JNK/p38 effects. Mouse liver and human-labelled L02 systems are distinguished; this supports the imported linkage-specific activity without asserting that every assay used purified human CYLD. Supporting Evidence: |
| GO:0061578 K63-linked deubiquitinase activity | TAS Reactome:R-HSA-5357845 | ACCEPT | Summary: CYLD is a modeled K63-chain hydrolase acting on RIPK1. Reason: The actual catalyst route5357845β5357880β5357750 includes CYLD741420, while phospho-CYLD is represented separately as a regulator. Independent biochemical evidence establishes K63 cleavage; the imported TAS is therefore consistent with a performed catalytic activity. |
| GO:0061578 K63-linked deubiquitinase activity | TAS Reactome:R-HSA-741411 | ACCEPT | Summary: The NEMO reaction assigns K63 deubiquitination to CYLD. Reason: Event 741411 identifies CYLD741420 through catalyst 741421 and describes reversal of RIP2-induced NEMO ubiquitination. The specific chain-cleavage activity is independently demonstrated for CYLD. This does not assign NEMO or RIPK2 functions to the enzyme. |
| GO:0061578 K63-linked deubiquitinase activity | TAS Reactome:R-HSA-936390 | ACCEPT | Summary: CYLD removes K63 ubiquitin in the RIG-I reaction. Reason: Event 936390 assigns catalyst 741421 to human CYLD741420 and describes RIG-I ubiquitin removal, consistent with the original antiviral study. The source summaryβs OTU-domain label is erroneous: CYLD is a USP/C19 enzyme. Preserve the correct catalytic annotation while explicitly separating that descriptive error. |
| GO:0061815 Met1-linked polyubiquitin deubiquitinase activity | EXP PMID:26997266 CYLD Limits Lys63- and Met1-Linked Ubiquitin at Receptor Com... | ACCEPT | Summary: CYLD hydrolyses Met1-linked ubiquitin chains. Reason: Actual 26997266 Results and linkage-selective restriction experiments support CYLD regulation of Met1 linkages on RIPK2; direct in-vitro cleavage is referenced in its supplementary Figure S1B, not separately viewed. Independently read 27591049 experiments use purified CYLD USP and Met1 substrates and demonstrate hydrolysis enhanced by SPATA2. CYLD activity must be distinguished from HOIPβs chain synthesis and OTULINβs separate substrate preference. |
| GO:0070064 proline-rich region binding | IPI PMID:15341735 The CAP-Gly domain of CYLD associates with the proline-rich ... | KEEP AS NON CORE | Summary: The third CAP-Gly domain binds a proline-rich NEMO region. Reason: The complete available abstract reports NMR evidence for association of the third CYLD CAP-Gly domain with a proline-rich sequence in NEMO/IKKgamma. The full original was not recovered, and no current literal Q9Y6K9 pair was returned. Retain the specifically curated positive binding class with these assay/construct limits rather than assuming all CAP-Gly domains bind the same ligand. Supporting Evidence: |
| GO:0070266 necroptotic process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: The inherited necroptotic role is supported in mouse signaling systems. Reason: The actual GO0070266 IBD is at on-path PTN002625528 and traces to genuine Q80TQ2 experimental donor records, including PMID27545878. Its original L929 experiments directly compare CYLD depletion in TNF/zVAD-induced death. Retain the contextual signaling-phase contribution; CYLD need not perform MLKL membrane disruption, and the mouse experiment is not presented as human IDA. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN002625528 SUPPORTS TRANSFER Actual on-path GO:0070266 IBD is grounded by current mouse experimental annotations, including direct L929 CYLD depletion in PMID:27545878. MGI:MGI:1921506 SUPPORTS TRANSFER Actual on-path GO:0070266 IBD is grounded by current mouse experimental annotations, including direct L929 CYLD depletion in PMID:27545878. Supporting Evidence: |
| GO:0070507 regulation of microtubule cytoskeleton organization | IMP PMID:20194890 CYLD regulates angiogenesis by mediating vascular endothelia... | ACCEPT | Summary: CYLD modulates microtubule organization and dynamics. Reason: The recovered original HUVEC Results and Figure 4 caption describe live GFP-tubulin tracking after CYLD knockdown, reduced growth/shortening time and altered centrosome orientation. Together with direct microtubule association and HDAC6-dependent acetylation, this supports a genuine regulatory role. Rac1 effects do not imply that CYLD itself is a Rac1 exchange factor. The local abstract directly states the microtubule-dynamics result. Figure and tracking details refer to the separately recovered original text, not to full text in this abstract-only cache. Supporting Evidence: PMID:20194890 Silencing of CYLD dramatically decreases microtubule dynamics in endothelial cells |
| GO:0070536 protein K63-linked deubiquitination | IBA GO_REF:0000033 | ACCEPT | Summary: K63-chain removal from protein substrates is a performed CYLD process. Reason: The actual GO0070536 IBD at PTN000931062 lies on the human target path and the literal mouse Q80TQ2 donor has a same-term IDA from PMID29291351. The original demonstrates CYLD-dependent K63 removal in hepatic models, and independent human CYLD enzymology corroborates the conserved process. No target-specific loss or unsupported similarity-only transfer is indicated. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000931062 SUPPORTS TRANSFER Actual on-path GO:0070536 IBD and exact mouse same-term IDA from PMID:29291351 support conserved chain removal. MGI:MGI:1921506 SUPPORTS TRANSFER Actual on-path GO:0070536 IBD and exact mouse same-term IDA from PMID:29291351 support conserved chain removal. |
| GO:0090090 negative regulation of canonical Wnt signaling pathway | IMP PMID:20227366 Loss of the tumor suppressor CYLD enhances Wnt/beta-catenin ... | KEEP AS NON CORE | Summary: CYLD suppresses canonical Wnt output through Dishevelled ubiquitin regulation. Reason: The complete available abstract directly reports enhanced beta-catenin signaling after CYLD loss and regulation of K63-linked Dishevelled ubiquitination. This supports the curated broad negative-regulation function with full-original access limits. It does not resolve the exact DVL3 construct required for the separate partner-specific binding row. Supporting Evidence: |
| GO:0097542 ciliary tip | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: The ciliary-tip assertion has a genuine mouse donor. Reason: The current Q80TQ2 same-term IDA cites PMID25134987, whose mouse ependymal cilia and tip localization were examined in the original. The human assertion remains an orthology transfer; human centrosomal staining alone is not substituted for the mouse ciliary-tip observation. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q80TQ2 SUPPORTS TRANSFER Literal current mouse same-term GO:0097542 experimental donor cites PMID:25134987. Actual mouse ciliary-tip localization; human centrosomal observations are separate. Supporting Evidence: |
| GO:1901223 negative regulation of non-canonical NF-kappaB signal transduction | IDA PMID:18313383 The structure of the CYLD USP domain explains its specificit... | UNDECIDED | Summary: The specific noncanonical NF-kappaB assertion is unresolved from this source. Reason: The 18313383 abstract supports general NF-kappaB/JNK regulation and K63-chain chemistry, but does not identify an assay isolating the noncanonical pathway. Full original Methods/Results could not be recovered. The directly read canonical RelA/TNF/NOD2 experiments in other papers do not authenticate this distinct claim. Preserve the exact IDA and use source-scoped uncertainty without denying possible noncanonical regulation. Supporting Evidence: |
| GO:1902017 regulation of cilium assembly | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: CYLD regulates basal-body docking and cilium assembly contextually. Reason: The exact mouse Q80TQ2 IMP donor cites PMID25134987. The original combines mouse ependymal defects with human RPE1 targeting/rescue experiments and a requirement for local catalytic competence. The engineered delta932 allele differs from both complete knockout and the official 953-residue splice product; different allele outcomes and possible compensation are retained as limits. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q80TQ2 SUPPORTS TRANSFER Literal current mouse same-term GO:1902017 experimental donor cites PMID:25134987. Mouse IMP plus human RPE1 targeting/rescue support a conserved regulatory role; engineered delta932 is not official isoform 2. Supporting Evidence: |
| GO:1903753 negative regulation of p38MAPK cascade | IDA PMID:29291351 The deubiquitinating enzyme cylindromatosis mitigates nonalc... | KEEP AS NON CORE | Summary: CYLD limits TAK1-dependent p38 signaling in hepatic models. Reason: The original links CYLD-dependent TAK1 K63 ubiquitination with p38 pathway activation in mouse liver and human-labelled L02 experiments. Retain this contextual negative-regulation assertion without inferring p38 itself as the directly deubiquitinated substrate. Supporting Evidence: |
| GO:1990108 protein linear deubiquitination | IDA PMID:26997266 CYLD Limits Lys63- and Met1-Linked Ubiquitin at Receptor Com... | ACCEPT | Summary: CYLD performs linear-chain editing on ubiquitinated signaling proteins. Reason: Actual 26997266 CYLD-depletion and linkage-restriction experiments resolve extended Met1-containing ubiquitin modifications on RIPK2, together with K63 changes. Independent purified CYLD Met1-chain hydrolysis in 27591049 supports the chemistry. The direct function belongs to CYLD; SPATA2 recruits/activates it and HOIP synthesizes the chains. Do not infer that every LUBAC substrate is processed identically: HOIP-chain control was OTULIN-dependent in the cited experiment. Supporting Evidence: PMID:26997266 CYLD limits extension of Lys63-Ub and Met1-Ub conjugated to RIPK2 |
| GO:1990108 protein linear deubiquitination | IDA PMID:27458237 SPATA2 promotes CYLD activity and regulates TNF-induced NF-ΞΊ... | ACCEPT | Summary: CYLD performs linear ubiquitin-chain removal in the SPATA2 study. Reason: The recovered original Results measure cleavage of defined M1-linked diubiquitin by purified FLAG-CYLD and enhanced activity with SPATA2. The construct numbering remains unresolved between reported C598A and the official sequence, so the performed reaction is retained without an intact-product-specific assignment. Supporting Evidence: |
| GO:1990108 protein linear deubiquitination | IDA PMID:27591049 SPATA2 Links CYLD to LUBAC, Activates CYLD, and Controls LUB... | ACCEPT | Summary: Reconstituted CYLDβSPATA2 complexes perform linear deubiquitination. Reason: The original directly measures M1-chain cleavage with CYLD USP and SPATA2 fragments and quantifies activation. This establishes the performed process; SPATA2 is the activator, while CYLD supplies hydrolysis. The shared USP fragment does not distinguish the two full-length official products. Supporting Evidence: |
| GO:2000493 negative regulation of interleukin-18-mediated signaling pathway | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: CYLD limits IL-18-mediated responses by controlling ligand maturation upstream. Reason: The exact Q80TQ2 mouse IMP donor cites PMID32424362. Cyld deubiquitinates NLRP6, reduces ASC assembly and excessive production of mature IL-18; catalytic rescue and IL-18 neutralization/genetic epistasis support the regulatory chain. The regulation definition does not require direct receptor binding. Retain the contextual inference to human CYLD, while making clear that the study did not measure a CYLD action at the IL-18 receptor and human tissue evidence was correlative. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q80TQ2 SUPPORTS TRANSFER Literal current mouse same-term GO:2000493 experimental donor cites PMID:32424362. The performed role is NLRP6 deubiquitination upstream of mature IL-18 production, not receptor binding. Supporting Evidence: |
| GO:2001238 positive regulation of extrinsic apoptotic signaling pathway | IMP PMID:21525013 TWEAK induces apoptosis through a death-signaling complex co... | KEEP AS NON CORE | Summary: CYLD supports extrinsic death signaling in a TWEAK-sensitive human carcinoma context. Reason: In HSC3 cells, CYLD depletion reduced TWEAK-induced RIP1/FADD recruitment to caspase-8 and attenuated loss of viability (PMID:21525013, Figure 6). Retain this contextual regulatory role as non-core. The experiment does not itself establish a direct CYLD catalytic substrate. Supporting Evidence: |
| GO:2001242 regulation of intrinsic apoptotic signaling pathway | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: A valid CYLD ancestral assertion captures contextual intrinsic-apoptosis regulation. Reason: PTN002625528 lies on the human CYLD path; its GO:2001242 IBD is grounded in human CYLD experimental evidence. Self-donor evidence is legitimate. Retain the inherited contextual role as non-core, with the same upstream-versus-mitochondrial scope limitation as the experimental assertion. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN002625528 SUPPORTS TRANSFER Actual on-path GO:2001242 IBD (current GAF row 26295) is grounded in human CYLD IMP PMID:21525013. Self grounding is legitimate; the mechanism is upstream death-complex regulation. UniProtKB:Q9NQC7 SUPPORTS TRANSFER Actual on-path GO:2001242 IBD (current GAF row 26295) is grounded in human CYLD IMP PMID:21525013. Self grounding is legitimate; the mechanism is upstream death-complex regulation. Supporting Evidence: |
| GO:2001242 regulation of intrinsic apoptotic signaling pathway | IMP PMID:21525013 TWEAK induces apoptosis through a death-signaling complex co... | KEEP AS NON CORE | Summary: CYLD regulates a death response with mitochondrial amplification. Reason: PMID:21525013 places the CYLD-sensitive death complex upstream of BID/BAX/BAK-dependent type-II apoptosis. This supports the existing broad regulation assertion as non-core. The paper measures CYLD-dependent complex assembly and viability, not CYLD-specific mitochondrial activity; no mitochondrial localization or direct mitochondrial substrate is inferred. Supporting Evidence: |
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Download this section (compressed HTML)Q: How do the two intact CYLD splice products differ in localization, SPATA2 activation and microtubule/HDAC6 regulation?
Q: Which CYLD substrates connect centrosomal recruitment to basal-body docking and cilium assembly, and how do truncation and complete-loss alleles differ?
Q: Which exact original assays support the DVL3 interaction, inner plasma-membrane location, noncanonical NF-kappaB regulation and the PMID:27458237 necroptosis annotation?
Experiment: Compare sequence-verified full-length 956- and 953-residue CYLD products under matched expression, measuring K63/M1 cleavage with SPATA2, HDAC6-dependent tubulin deacetylation and centrosomal localization. Include catalytic and N-terminal interface controls to distinguish the two mechanisms.
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