Affinage

CYLD

Ubiquitin carboxyl-terminal hydrolase CYLD · UniProt Q9NQC7

Length
956 aa
Mass
107.3 kDa
Annotated
2026-06-09
100 papers in source corpus 40 papers cited in narrative 40 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CYLD is a deubiquitinase that acts as a central negative regulator of inflammatory and survival signaling, removing predominantly K63-linked (and in some contexts K48- and M1-linked) ubiquitin chains from a broad repertoire of signaling proteins to function as a tumor suppressor (PMID:12917689). In the canonical NF-κB and MAPK axes it deubiquitinates the TRAF/TAK1 module—TRAF2 and TRAF6 to dampen TNFR-family and RANK signaling (PMID:12917689, PMID:18382763) and TAK1 to limit JNK and IKKβ activation (PMID:17548520)—and extends this control to RIG-I antiviral signaling, RIPK2, and the AP-1 components c-Jun and c-Fos (PMID:18467330, PMID:26834734, PMID:21478324). CYLD partitions inflammatory versus death outcomes by editing RIPK1 ubiquitination within the necrosome and at death-signaling Complex II, governing necroptosis and TNF-induced cell death (PMID:24098568, PMID:34887354). Beyond cytokine signaling it restrains inflammasome activity by deubiquitinating NLRP6 and, via centrosomal PLK4, the NEK7–NLRP3 axis (PMID:32424362, PMID:31762063). A second, frequently catalysis-independent arm of CYLD function operates on the cytoskeleton: through its CAP-Gly ubiquitin-binding domains it associates with α-tubulin and microtubule plus-end factor EB1, enhances microtubule assembly, and inhibits HDAC6 to raise tubulin acetylation, thereby controlling cell migration, cell-cycle progression, ciliogenesis (via Cep70 and PCM1), and gap-junction assembly (via plakoglobin) (PMID:18222923, PMID:19893491, PMID:24552808, PMID:25342559, PMID:31067453, PMID:36577382). CYLD activity is tightly regulated by IKK-family phosphorylation that is inhibitory at Ser418/Ser568 and degradation-targeting at Ser432/436 through SCFβ-TRCP, by MALT1 proteolytic cleavage, by SUMOylation, and by allosteric activation through the adaptor SPATA2, which recruits CYLD to the TNF receptor complex and the centrosome (PMID:15870263, PMID:34610306, PMID:24961988, PMID:21448133, PMID:24909169, PMID:27458237). It additionally controls p53 stabilization, the CDK inhibitor p18, and Bcl-3 nuclear accumulation, linking its deubiquitinase activity to growth-suppressive and proliferative checkpoints (PMID:27561390, PMID:33654169, PMID:16713561).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2003 High

    Established CYLD's foundational identity as a deubiquitinase that restrains NF-κB signaling, explaining how its loss drives tumorigenesis.

    Evidence Deubiquitinase activity assays, RNAi, and Co-IP across CD40/XEDAR/EDAR receptor systems with NF-κB reporters

    PMID:12917689

    Open questions at the time
    • Did not resolve ubiquitin chain-type specificity in vivo
    • Direct enzymatic action on TRAF2/TRAF6 chains versus indirect effects not fully separated
  2. 2005 High

    Defined the first regulatory feedback on CYLD, showing IKKγ/NEMO-dependent phosphorylation transiently silences its activity to permit signal-induced TRAF2 ubiquitination.

    Evidence In vivo phosphorylation assays with IKK subunit overexpression/knockdown and TRAF2 ubiquitination readout

    PMID:15870263

    Open questions at the time
    • Precise phospho-sites and how phosphorylation alters catalysis not mapped
    • Kinase responsible for direct phosphorylation versus complex effects unclear
  3. 2006 High

    Revealed context-dependent and even positive roles for CYLD—deubiquitinating Bcl-3 to block keratinocyte proliferation and deubiquitinating Lck to promote TCR signaling—beyond a uniform negative regulator.

    Evidence CYLD knockout mice, subcellular fractionation/live imaging, Co-IP, and T cell development analysis

    PMID:16501569 PMID:16713561

    Open questions at the time
    • Molecular basis of stimulus-induced CYLD perinuclear translocation unresolved
    • How CYLD distinguishes positive vs negative substrate outcomes not defined
  4. 2007 High

    Extended CYLD substrate control to TAK1 and uncovered a deubiquitinase-independent cytoskeletal role, broadening its mechanism into both signaling and microtubule biology.

    Evidence Knockout mice and ubiquitination/kinase assays for TAK1; immunofluorescence, Plk1 Co-IP, and Drosophila dTRAF2 genetics for cytoskeletal/developmental roles

    PMID:17495026 PMID:17548520 PMID:17765686

    Open questions at the time
    • Mechanistic link between CYLD-Plk1 interaction and mitotic entry not reconstituted
    • How a single enzyme coordinates signaling and microtubule functions unclear
  5. 2008 High

    Mapped CYLD's cytoskeletal mechanism to its first CAP-Gly domain that binds microtubules and enhances tubulin polymerization, and added RIG-I antiviral and TRAF6/RANK osteoclast substrates.

    Evidence In vitro microtubule co-sedimentation and polymerization assays with CAP-Gly mutants; knockout cells/mice with RIG-I and TRAF6 ubiquitination assays

    PMID:18222923 PMID:18382763 PMID:18467330

    Open questions at the time
    • Whether CAP-Gly microtubule binding requires ubiquitin recognition not resolved
    • Recruitment adaptor p62 mechanism for TRAF6 not generalized
  6. 2009 High

    Integrated CYLD's cytoskeletal and proliferation control by showing CAP-Gly-mediated HDAC6 inhibition raises acetylated tubulin to gate G1/S and cytokinesis, and linked Snail1 repression of CYLD to Bcl-3-driven oncogenesis.

    Evidence Co-IP, immunofluorescence, cell-cycle analysis, HDAC6 inhibition assays; Snail1 expression/knockdown with CYLD rescue in tumor models

    PMID:19124656 PMID:19893491

    Open questions at the time
    • Whether HDAC6 is a direct CYLD binding partner vs indirect target not fully defined
    • Catalytic-independent vs dependent contributions to each phenotype not cleanly separated
  7. 2011 High

    Established multilayered regulation and substrate logic—MALT1 proteolytic cleavage inactivates CYLD to permit JNK activation, the Itch-CYLD complex sequentially edits TAK1 from K63 to K48, and CYLD blocks AP-1 by deubiquitinating c-Jun/c-Fos.

    Evidence MALT1 protease assays, complex reconstitution with domain-specific CYLD mutants, in vitro and in vivo ubiquitination assays

    PMID:21448133 PMID:21478324 PMID:22057290

    Open questions at the time
    • Physiological balance between cleavage and editing not quantified
    • How CYLD partner choice (Itch vs others) is determined unclear
  8. 2014 High

    Greatly expanded CYLD's substrate and regulatory landscape—p53 stabilization, ciliogenesis via Cep70, EB1 plus-end coordination, HDAC7-dependent transcription, MIB2/Notch, SUMOylation and β-TRCP phosphodegron control—cementing it as a hub of both catalytic and non-catalytic functions.

    Evidence Knockout/catalytic-mutant mice, ubiquitin chain-restriction analysis, ChIP, yeast two-hybrid, SUMOylation and phospho-mutant assays

    PMID:24552808 PMID:24811579 PMID:24909169 PMID:24961988 PMID:25342559 PMID:25565632 PMID:27561390

    Open questions at the time
    • Relative in vivo importance of the many substrates unranked
    • Some interactions rest on single-lab Co-IP without reciprocal validation
  9. 2015 High

    Demonstrated pathway-selective output by showing CYLD-TRAF2 deubiquitination maintains hematopoietic stem cell quiescence through p38MAPK rather than NF-κB.

    Evidence Conditional and TRAF2-binding-mutant knockout mice with quiescence/repopulation assays and p38MAPK inhibitor rescue

    PMID:25824820

    Open questions at the time
    • Mechanism directing TRAF2 deubiquitination to p38 vs NF-κB output not defined
    • Direct p38 substrate connection not established
  10. 2016 High

    Identified SPATA2 as the direct allosteric activator and recruitment adaptor for CYLD at the TNF receptor complex, explaining how CYLD is positioned and switched on.

    Evidence Mass spectrometry, Co-IP, in vitro deubiquitinase assay with SPATA2, and Complex I isolation

    PMID:27458237

    Open questions at the time
    • Structural basis of PUB-domain allosteric activation not solved here
    • Whether SPATA2 governs all CYLD substrate engagements unknown
  11. 2019 High

    Connected the SPATA2-CYLD module to centrosome and inflammasome biology via PLK4-NEK7-NLRP3 and PCM1-dependent centriolar satellite proteostasis, and extended cytoskeletal roles to neuronal dendrite and spine formation.

    Evidence Co-IP, substrate ubiquitination and phosphorylation assays, SPATA2/PCM1 knockout/knockdown, and neuronal domain-mutant imaging

    PMID:31001844 PMID:31067453 PMID:31762063

    Open questions at the time
    • Coordination of centrosomal vs receptor-complex CYLD pools unclear
    • PCM1/Cep70 regulation rest on single-lab evidence
  12. 2020 High

    Linked CYLD regulation to disease through NLRP6 inflammasome control, IKK-reversible RIPK1 editing in leukemic cell death, and a gain-of-function M719V variant tied to neurological disease and autophagy.

    Evidence Knockout mouse infection models with IL-18 readout, IKK inhibitor/DISC studies, and in vitro deubiquitinase plus NF-κB/autophagy assays of the variant

    PMID:32024820 PMID:32185393 PMID:32424362

    Open questions at the time
    • How elevated catalytic activity of M719V perturbs autophagosome-lysosome fusion mechanistically unclear
    • In vivo consequences of IKK-reversal in normal tissue not addressed
  13. 2021 High

    Refined the activation logic—defining CAP-Gly3 as essential for catalysis, a Ser418/Ser568 phosphorylation switch activating CYLD toward K63 chains, and a CYLD-SPATA2-LUBAC ubiquitin-editing complex—and added ERK1/2, p18, plakoglobin, and NoxO1 as substrates with K63 or K48 specificity.

    Evidence Biochemical CAP-Gly/phospho-mutant deubiquitinase assays, in vitro ubiquitination/site-mapping with TRIM15, half-life and ubiquitination assays, and KO mouse cardiac phenotyping

    PMID:33654169 PMID:34497368 PMID:34610306 PMID:34742871 PMID:36577382

    Open questions at the time
    • Structural model of phospho-activated CYLD not provided
    • Switching between K63 and K48 chain editing on different substrates mechanistically unresolved
  14. 2022 High

    Tied the SPATA2-CYLD axis to cell-death and metabolic pathologies, regulating NCOA4-dependent ferritinophagy/ferroptosis and SHARPIN-dependent Complex II death signaling.

    Evidence Co-IP, NCOA4 ubiquitination assays, SPATA2 knockdown in cardiomyocyte/mouse models; genetic double-knockout and Complex II immunoprecipitation

    PMID:34887354 PMID:36195186

    Open questions at the time
    • NCOA4 ferritinophagy axis rests on single-lab evidence
    • Tissue-specific determinants of pro-death versus pro-survival CYLD output not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How CYLD's catalytic deubiquitinase functions and its catalysis-independent CAP-Gly/microtubule and transcriptional roles are integrated, and which of its many substrates dominate in any given tissue, remains unresolved.
  • No unified structural model linking phospho-regulation, SPATA2 binding, and chain-type selectivity
  • Substrate hierarchy across tissues unranked
  • Mechanistic basis of catalysis-independent functions incompletely defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 8 GO:0016787 hydrolase activity 4 GO:0008092 cytoskeletal protein binding 3 GO:0098772 molecular function regulator activity 2
Localization
GO:0005815 microtubule organizing center 3 GO:0005856 cytoskeleton 3 GO:0005829 cytosol 2 GO:0005929 cilium 2
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 4 R-HSA-1640170 Cell Cycle 3 R-HSA-1852241 Organelle biogenesis and maintenance 3 R-HSA-5357801 Programmed Cell Death 2
Partners
EB1HDAC6ITCHPLK1SPATA2TAK1TRAF2TRAF6
Complex memberships
CYLD-SPATA2-LUBAC ubiquitin-editing complexItch-CYLD complexTNF receptor signaling complex (Complex I)

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 CYLD is a deubiquitinating enzyme that negatively regulates NF-κB activation by removing ubiquitin chains from TRAF2 and TRAF6, thereby inhibiting signaling downstream of TNFR family members CD40, XEDAR, and EDAR. Loss of CYLD deubiquitinating activity correlates with tumorigenesis. Deubiquitinase activity assay, RNA interference knockdown, Co-immunoprecipitation, NF-κB reporter assays Nature High 12917689
2006 CYLD deubiquitinates Bcl-3 in the perinuclear region, preventing nuclear accumulation of Bcl-3/p50 and Bcl-3/p52 complexes and thereby blocking cyclin D1-dependent keratinocyte proliferation. TPA or UV triggers translocation of CYLD from cytoplasm to perinuclear region to execute this function. This pathway is distinct from CYLD's regulation of TRAF2/p65-p50 NF-κB survival signaling. CYLD knockout mice, Co-immunoprecipitation, subcellular fractionation/live imaging, chemical induction (TPA/UV), cyclin D1 expression assays Cell High 16713561
2005 CYLD is phosphorylated by IκB kinase gamma (IKKγ/NEMO)-dependent signaling in response to cellular stimuli, and this phosphorylation transiently inhibits CYLD's deubiquitinase activity, allowing signal-induced TRAF2 ubiquitination and downstream IKK activation. In vivo phosphorylation assays, IKK subunit overexpression and knockdown, TRAF2 ubiquitination assays Molecular and cellular biology High 15870263
2006 CYLD physically interacts with active Lck and promotes recruitment of active Lck to its substrate Zap70 during T cell receptor signaling in thymocytes. CYLD also removes both K48- and K63-linked polyubiquitin chains from Lck, positively regulating proximal TCR signaling and T cell development. Co-immunoprecipitation, CYLD knockout mice, T cell development analysis, ubiquitin chain-type analysis Nature immunology High 16501569
2007 CYLD deubiquitinates and inactivates TAK1 (transforming growth factor-β-activated kinase 1), inhibiting TAK1 ubiquitination and autoactivation, thereby suppressing downstream JNK and IKKβ activation in T cells. CYLD knockout mice, Co-immunoprecipitation, TAK1 ubiquitination and kinase activity assays The Journal of experimental medicine High 17548520
2007 CYLD localizes to microtubules during interphase and to the midbody during telophase, and its protein levels decrease as cells exit mitosis. CYLD physically interacts with Plk1 and shares similar loss-of-function and overexpression phenotypes, implicating CYLD in regulating timely mitotic entry. Immunofluorescence/live cell imaging, Co-immunoprecipitation, loss-of-function and overexpression experiments, cell cycle analysis Proceedings of the National Academy of Sciences of the United States of America Medium 17495026
2007 Drosophila CYLD (dCYLD) deubiquitinates dTRAF2, preventing its ubiquitin-mediated proteolytic degradation, and thereby regulates TNF-induced JNK activation and JNK-dependent cell death. dTRAF2 acts downstream of the TNF receptor Wengen and upstream of the JNKK kinase dTAK1. Drosophila genetic mutants, transgenic flies with wild-type and catalytic-dead dCYLD, dTRAF2 ubiquitination assay, epistasis analysis Developmental cell High 17765686
2008 CYLD negatively regulates RANK signaling and osteoclastogenesis by inhibiting TRAF6 ubiquitination. CYLD physically interacts with the signaling adaptor p62, which recruits CYLD to TRAF6. CYLD knockout mice, RANKL-induced osteoclast differentiation assays, Co-immunoprecipitation, TRAF6 ubiquitination assays The Journal of clinical investigation High 18382763
2008 CYLD deubiquitinates RIG-I (a cytoplasmic RNA sensor) and inhibits its ubiquitination, thereby suppressing RIG-I-mediated activation of IKKε/TBK1 and IFN-β promoter induction during viral infection. CYLD knockout cells, RIG-I ubiquitination assay, IFN-β reporter assay, IKKε/TBK1 kinase activation assay The Journal of biological chemistry Medium 18467330
2008 CYLD associates with microtubules both in cells and in vitro through its first CAP-Gly domain. CYLD enhances tubulin polymerization by lowering the critical concentration for microtubule assembly and promotes microtubule regrowth after nocodazole washout. The first CAP-Gly domain is required for CYLD-dependent cell migration. In vitro microtubule co-sedimentation assay, tubulin polymerization assay, CAP-Gly domain deletion mutants, nocodazole washout assay, wound healing assay The Journal of biological chemistry High 18222923
2009 CYLD controls cell cycle progression at G1/S and cytokinesis by associating with α-tubulin and microtubules through its CAP-Gly domains. CYLD inhibits HDAC6, increasing perinuclear acetylated α-tubulin levels, which facilitates CYLD interaction with Bcl-3 to delay G1-to-S transition. CYLD also interacts with HDAC6 at the midbody to regulate cytokinesis in a deubiquitinase-independent manner. Co-immunoprecipitation, immunofluorescence, cell cycle analysis, HDAC6 inhibition assays, CYLD-Bcl-3 interaction assay The EMBO journal High 19893491
2009 Snail1 transcriptionally represses CYLD expression in melanoma. As a consequence of CYLD repression, BCL-3 translocates to the nucleus, activating Cyclin D1 and N-cadherin promoters and driving proliferation and invasion. Snail1 expression/knockdown, CYLD rescue experiments, in vitro and in vivo tumor models, tissue microarray analysis The Journal of experimental medicine Medium 19124656
2010 CYLD knockdown significantly impairs angiogenesis by blocking endothelial cell spreading, migration, and polarity. CYLD regulates microtubule dynamics in endothelial cells and activates Rac1, with Rac1 activation being an important downstream mechanism for CYLD's role in endothelial cell migration. siRNA knockdown, tube formation assay, 3D capillary sprouting assay, in vivo angioreactor assay, microtubule dynamics imaging, Rac1 activation assay Blood Medium 20194890
2011 MALT1 proteolytically cleaves and inactivates CYLD following TCR activation in T cells and by oncogenic API2-MALT1. CYLD cleavage by MALT1 is specifically required for JNK activation and inducible expression of a subset of TCR-responsive genes. MALT1 protease activity assays, CYLD cleavage detection, JNK activation assay, gene expression analysis, MALT1 inhibitor studies The EMBO journal High 21448133
2011 Itch (E3 ligase) and CYLD form a complex via WW-PPXY motif interactions. The Itch-CYLD complex sequentially removes K63-linked ubiquitin chains (via CYLD) and then catalyzes K48-linked ubiquitination (via Itch) on TAK1, terminating inflammatory TNF signaling. CYLD(Y485A) mutant unable to associate with Itch cannot block sustained TAK1 activation. Co-immunoprecipitation, in vitro deubiquitination assay, TAK1 ubiquitination assay, CYLD mutant reconstitution in CYLD−/− macrophages, cytokine production assay Nature immunology High 22057290
2011 CYLD deubiquitinates c-Jun and c-Fos, removing K63-linked ubiquitin chains from these AP-1 components. Catalytically inactive CYLD mutant (CYLDm) increases K63 ubiquitination on c-Jun and c-Fos, leading to sustained AP-1 activation via JNK. CYLD thus blocks JNK/AP-1 signaling at multiple levels. In vivo ubiquitination assay for c-Jun and c-Fos, JNK activation assay, transgenic mouse skin tumorigenesis model, JNK inhibitor treatment Cancer prevention research (Philadelphia, Pa.) Medium 21478324
2013 CYLD regulates RIP1 ubiquitination specifically within the NP-40 insoluble necrosome (not at the TNFR-1 signaling complex) during TNFα-induced programmed necrosis. Increased RIP1 ubiquitination in the necrosome in CYLD−/− cells impairs RIP1 and RIP3 phosphorylation, inhibiting kinase activation required for necroptosis. CYLD knockout cells, RIP1 ubiquitination assay in necrosome fraction, RIP1-RIP3 phosphorylation assay, SMAC mimetic and cycloheximide sensitization experiments PloS one High 24098568
2014 CYLD mediates ciliogenesis by deconjugating polyubiquitin chains from centrosomal protein Cep70, which is required for Cep70 to interact with γ-tubulin and localize at the centrosome. Additionally, CYLD-mediated inhibition of HDAC6 promotes tubulin acetylation, constituting a second mechanism for ciliary assembly. CYLD knockout mice (polydactyly, ciliary defect phenotype), Co-immunoprecipitation (Cep70-γ-tubulin), Cep70 ubiquitination assay, HDAC6 inhibitor rescue experiments Cell research High 25342559
2014 CYLD interacts with and deubiquitinates p53, facilitating p53 stabilization in response to genotoxic stress by removing K63-linked ubiquitin chains (and thereby indirectly preventing K48-linked degradation). Loss of CYLD catalytic activity impairs DNA damage-induced p53 stabilization and activation. Co-immunoprecipitation, p53 ubiquitination assay, ubiquitin chain-restriction analysis, CYLD catalytic mutant knock-in mice, C. elegans CEP-1/p53 epistasis Nature communications High 27561390
2014 CYLD coordinates with EB1 at microtubule plus ends to regulate microtubule dynamics and cell migration. The CYLD-EB1 interaction increases upon stimulation of cell migration. CYLD and EB1 act in concert to regulate tail retraction, centrosome reorientation, leading-edge microtubule stabilization, and microtubule nucleation. Yeast two-hybrid screening, Co-immunoprecipitation, in vitro microtubule assembly assay, live cell imaging of migration, centrosome reorientation assay Cell cycle (Georgetown, Tex.) Medium 24552808
2014 CYLD interacts with HDAC7 to remove HDAC7 from the HGF promoter in hepatic stellate cells, inducing HGF gene transcription independently of CYLD's deubiquitinating activity. Co-immunoprecipitation, ChIP assay, CYLD catalytic-dead mutant experiments, CYLD−/− mice with HGF measurement Hepatology (Baltimore, Md.) Medium 24811579
2014 CYLD deubiquitinating activity is inhibited by SUMOylation. Retinoic acid-induced SUMOylation of CYLD blocks its deubiquitinase activity against TRAF2 and TRAF6, facilitating NF-κB signaling during neuroblastoma differentiation. SUMOylation assay, CYLD deubiquitinase activity assay with TRAF2/TRAF6 substrates, non-SUMOylatable CYLD mutant overexpression, NF-κB activation assay Oncogene Medium 24909169
2014 CYLD interacts with MIB2 (a ubiquitin ligase), stabilizing MIB2 protein levels and reducing JAG2 expression, thereby attenuating Notch signaling. CYLD gene silencing increases JAG2 expression and upregulates Notch signaling. Proteomics/mass spectrometry to identify interactors, Co-immunoprecipitation, siRNA knockdown, Notch target gene expression analysis, primary tumor cell cultures Oncotarget Medium 25565632
2015 CYLD maintains hematopoietic stem cell (HSC) quiescence through deubiquitination of TRAF2. This function operates through the p38MAPK pathway (not NF-κB), and pharmacological inhibition of p38MAPK rescues the CYLD-loss HSC phenotype of increased cycling and loss of repopulation potential. Conditional CYLD KO mice, CYLD-TRAF2 binding mutant mice, HSC quiescence assays, transplantation/repopulation assays, p38MAPK inhibitor treatment The Journal of experimental medicine High 25824820
2014 SCFβ-TRCP E3 ligase promotes ubiquitination and degradation of CYLD in a manner dependent on prior IKK-mediated phosphorylation of CYLD at Ser432/Ser436. β-TRCP depletion causes CYLD accumulation and TRAF6 deubiquitination, suppressing osteoclastogenesis. Co-immunoprecipitation, ubiquitination assays, phosphorylation-site mutants, β-TRCP siRNA, TRAF6 ubiquitination assay, osteoclast differentiation assay Oncotarget Medium 24961988
2016 SPATA2 directly interacts with CYLD via its PUB domain and acts as an allosteric activator of CYLD's K63- and M1-deubiquitinase activity. SPATA2 is required for recruitment of CYLD to the TNF receptor signaling complex, and its loss attenuates TNF-induced NF-κB/MAPK signaling while also reducing Complex II formation and apoptosis. Mass spectrometry screen, Co-immunoprecipitation, in vitro deubiquitinase activity assay with SPATA2, TNF signaling complex (Complex I) isolation EMBO reports High 27458237
2016 CYLD removes K63-linked ubiquitin chains from RIPK2, inhibiting RIPK2 K63-ubiquitination and impairing NF-κB and ERK1/2 activation in Listeria-infected macrophages, thereby reducing antibacterial immune responses. Co-immunoprecipitation, RIPK2 ubiquitination assay, CYLD KO macrophages, siRNA knockdown, NF-κB and ERK activation assays Frontiers in immunology Medium 26834734
2019 CYLD is recruited by SPATA2 to the centrosome where it deubiquitinates PLK4 (master regulator of centrosome duplication). Deubiquitination of PLK4 facilitates its phosphorylation of NEK7 at Ser204, which attenuates NEK7-NLRP3 interaction and suppresses NLRP3 inflammasome activation. Co-immunoprecipitation, PLK4 ubiquitination assay, NEK7 phosphorylation assay, NLRP3 inflammasome activation assay, SPATA2 KO macrophages, PLK4 inhibitor/shRNA The EMBO journal High 31762063
2019 CYLD promotes the proteostasis of centriolar satellites by deubiquitinating PCM1 scaffold protein and protecting it from MIB1-mediated proteasomal degradation. CYLD knockdown promotes PCM1 degradation and dismantling of centriolar satellites, impairing ciliogenesis. Unbiased proteomic screen of CYLD binding partners, Co-immunoprecipitation, PCM1 ubiquitination assay, MIB1 E3 ligase assay, siRNA knockdown, cilia formation assay Cell reports Medium 31067453
2020 CYLD deubiquitinates NLRP6, and this deubiquitination inhibits the NLRP6-ASC inflammasome complex, preventing excessive IL-18 maturation in the colonic mucosa. Co-immunoprecipitation, NLRP6 ubiquitination assay, CYLD knockout mice with Citrobacter rodentium infection, IL-18 maturation assay Nature immunology High 32424362
2020 A gain-of-function CYLD missense variant (M719V) exhibits significantly increased K63 deubiquitinase activity relative to wild-type. Overexpression of CYLD-M719V leads to more potent NF-κB inhibition and impairment of autophagosome fusion to lysosomes. In vitro deubiquitinase activity assay with Wilcoxon signed-rank test, NF-κB luciferase reporter assay, autophagy flux assay in HEK293 cells Brain : a journal of neurology Medium 32185393
2021 TRIM15 is a K63-ubiquitin ligase for ERK1/2 and CYLD is the deubiquitinase that removes K63-linked chains from ERK1/2. K63-linked polyubiquitination of ERK1/2 by TRIM15 enhances ERK interaction with and activation by MEK. TRIM15 and CYLD regulate ERK ubiquitination at defined lysine residues through mutually exclusive interactions. In vitro ubiquitination and deubiquitinase assays, ERK ubiquitination site mapping by mutagenesis, Co-immunoprecipitation, ERK activation (MEK interaction) assay Nature cell biology High 34497368
2021 Two CAP-Gly domains of CYLD function as ubiquitin-binding domains, with CAP-Gly3 required for CYLD deubiquitinase activity and regulation of immune receptor signaling. A phosphorylation switch outside the catalytic USP domain (Ser568, a TNF-regulated site, acting in concert with Ser418) activates CYLD toward K63-linked polyubiquitin. Phosphorylated CYLD together with SPATA2 and LUBAC functions as a ubiquitin-editing complex. Structural/biochemical analysis of CAP-Gly domains, phosphoproteomic identification of Ser568, in vitro deubiquitinase activity assays with phospho-mimetic mutants, immune receptor signaling assays Cell reports High 34610306
2021 CYLD stabilizes p18 (CDK inhibitor) by binding to p18 and removing K48-linked polyubiquitin chains, preventing p18 proteasomal degradation and maintaining G1/S cell cycle arrest. Co-immunoprecipitation, p18 ubiquitination assay (K48 chain type), p18 half-life assay (CHX chase), CYLD KO/knockdown cell cycle analysis, in vivo xenograft NPJ precision oncology Medium 33654169
2021 CYLD is required for SHARPIN-deficient mouse phenotype (dermatitis, spleen architecture disruption). In SHARPIN-deficient cells, impaired CYLD phosphorylation at Ser418 (which normally inhibits CYLD) leads to enhanced CYLD-dependent RIPK1 recruitment to death-signaling Complex II following TNF stimulation, causing myeloid cell death and inflammation. Genetic double KO (Sharpin/CYLD), myeloid-specific conditional Cyld deletion, Complex II immunoprecipitation, CYLD Ser418 phosphorylation analysis Proceedings of the National Academy of Sciences of the United States of America High 34887354
2022 CYLD deubiquitinates plakoglobin by removing K63-linked polyubiquitin chains. Deubiquitinated plakoglobin shows enhanced interaction with the desmoplakin/EB1 complex at microtubule plus ends, promoting microtubule-dependent transport of connexin 43 (Cx43) to the cell membrane for gap junction assembly at the intercalated disc. Co-immunoprecipitation, plakoglobin ubiquitination assay (K63), CYLD KO mice (cardiac gap junction, fibrosis phenotype), microtubule transport assay, Cx43 membrane targeting assay Cell reports High 36577382
2022 SPATA2/CYLD pathway regulates ferritinophagy in cardiomyocytes by controlling the ubiquitination and degradation of NCOA4 (the ferritinophagy cargo receptor). CYLD/SPATA2-mediated deubiquitination of NCOA4 enhances ferritin autophagy, leading to intracellular iron overload and ferroptosis. Co-immunoprecipitation (SPATA2-CYLD interaction), NCOA4 ubiquitination assay, SPATA2 knockdown, doxorubicin-treated cardiomyocyte and mouse models, ferritinophagy and ferroptosis readouts Chemico-biological interactions Medium 36195186
2019 CYLD promotes dendritic growth in neurons through regulation of α-tubulin acetylation. CYLD also promotes postsynaptic spine formation through a mechanism dependent on its first microtubule-binding domain but independent of tubulin acetylation, indicating distinct molecular mechanisms for dendritic growth vs. spine formation. CYLD overexpression and knockdown in hippocampal neurons, tubulin acetylation-site mutants (co-expression rescue), CYLD domain truncation/mutation analysis, live cell imaging of dendrites and spines The European journal of neuroscience Medium 31001844
2020 CYLD phosphorylation (inhibitory modification) is mediated by TBK1/IKKε and IKKβ, and its reversal by IKK inhibitors restores CYLD deubiquitinase activity toward RIPK1, reducing RIPK1 K63-ubiquitination and triggering RIPK1 recruitment to the DISC and cell death in ATLL cells. IKK inhibitors (MRT67307, TPCA), kinase-inactive TBK1 overexpression, CYLD phosphorylation assay, RIPK1 ubiquitination assay, DISC immunoprecipitation, CYLD KO controls Cell death & disease Medium 32024820
2021 CYLD overexpression promotes K48-linked ubiquitination and degradation of NoxO1 (NADPH oxidase organizer 1), reducing NoxO1 protein half-life and suppressing excessive ROS generation. CYLD-mediated NoxO1 destabilization suppresses prostate cancer cell proliferation and tumor growth. CRISPR/Cas9 DUB-KO library screen, Co-immunoprecipitation, NoxO1 ubiquitination assay, CHX half-life assay, CYLD CRISPR KO in prostate cancer cells, xenograft tumor assay Cancer letters Medium 34742871

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 CYLD is a deubiquitinating enzyme that negatively regulates NF-kappaB activation by TNFR family members. Nature 824 12917689
2006 Cyld inhibits tumor cell proliferation by blocking Bcl-3-dependent NF-kappaB signaling. Cell 416 16713561
2010 CYLD: a tumor suppressor deubiquitinase regulating NF-kappaB activation and diverse biological processes. Cell death and differentiation 357 19373246
2013 CYLD deubiquitinates RIP1 in the TNFα-induced necrosome to facilitate kinase activation and programmed necrosis. PloS one 273 24098568
2017 CYLD, A20 and OTULIN deubiquitinases in NF-κB signaling and cell death: so similar, yet so different. Cell death and differentiation 221 28362430
2007 Deubiquitinating enzyme CYLD negatively regulates the ubiquitin-dependent kinase Tak1 and prevents abnormal T cell responses. The Journal of experimental medicine 216 17548520
2006 Regulation of T cell development by the deubiquitinating enzyme CYLD. Nature immunology 194 16501569
2009 Down-regulation of CYLD expression by Snail promotes tumor progression in malignant melanoma. The Journal of experimental medicine 186 19124656
2011 T-cell receptor-induced JNK activation requires proteolytic inactivation of CYLD by MALT1. The EMBO journal 183 21448133
2005 Regulation of the deubiquitinating enzyme CYLD by IkappaB kinase gamma-dependent phosphorylation. Molecular and cellular biology 165 15870263
2008 Deubiquitinating enzyme CYLD negatively regulates RANK signaling and osteoclastogenesis in mice. The Journal of clinical investigation 162 18382763
2011 The E3 ligase Itch and deubiquitinase Cyld act together to regulate Tak1 and inflammation. Nature immunology 146 22057290
2009 CYLD negatively regulates cell-cycle progression by inactivating HDAC6 and increasing the levels of acetylated tubulin. The EMBO journal 145 19893491
2006 Reduced expression of CYLD in human colon and hepatocellular carcinomas. Carcinogenesis 142 16774947
2007 The tumor suppressor CYLD regulates entry into mitosis. Proceedings of the National Academy of Sciences of the United States of America 116 17495026
2008 The tumor suppressor CYLD regulates microtubule dynamics and plays a role in cell migration. The Journal of biological chemistry 114 18222923
2008 Regulation of IkappaB kinase-related kinases and antiviral responses by tumor suppressor CYLD. The Journal of biological chemistry 107 18467330
2014 CYLD mediates ciliogenesis in multiple organs by deubiquitinating Cep70 and inactivating HDAC6. Cell research 106 25342559
2011 CYLD: a deubiquitination enzyme with multiple roles in cancer. Future oncology (London, England) 102 21345146
2010 Ubiquitin chain cleavage: CYLD at work. Trends in biochemical sciences 102 20347313
2016 SPATA2 promotes CYLD activity and regulates TNF-induced NF-κB signaling and cell death. EMBO reports 100 27458237
2007 Tumor suppressor CYLD regulates JNK-induced cell death in Drosophila. Developmental cell 97 17765686
2020 Deubiquitination of NLRP6 inflammasome by Cyld critically regulates intestinal inflammation. Nature immunology 93 32424362
2007 Regulation of B cell homeostasis and activation by the tumor suppressor gene CYLD. The Journal of experimental medicine 86 17923499
2009 Update of cylindromatosis gene (CYLD) mutations in Brooke-Spiegler syndrome: novel insights into the role of deubiquitination in cell signaling. Human mutation 82 19462465
2019 PLK4 deubiquitination by Spata2-CYLD suppresses NEK7-mediated NLRP3 inflammasome activation at the centrosome. The EMBO journal 81 31762063
2015 CYLD-mediated signaling and diseases. Current drug targets 81 25342597
2021 TRIM15 and CYLD regulate ERK activation via lysine-63-linked polyubiquitination. Nature cell biology 76 34497368
2010 CYLD regulates angiogenesis by mediating vascular endothelial cell migration. Blood 74 20194890
2020 CYLD is a causative gene for frontotemporal dementia - amyotrophic lateral sclerosis. Brain : a journal of neurology 73 32185393
2014 Clinical significance of CYLD downregulation in breast cancer. Breast cancer research and treatment 70 24398777
2013 CYLD controls c-MYC expression through the JNK-dependent signaling pathway in hepatocellular carcinoma. Carcinogenesis 68 24104553
2008 Tumor suppressor CYLD: negative regulation of NF-kappaB signaling and more. Cellular and molecular life sciences : CMLS 67 18193168
2007 Deubiquitinating enzyme CYLD regulates the peripheral development and naive phenotype maintenance of B cells. The Journal of biological chemistry 62 17392286
2022 Novel role of macrophage TXNIP-mediated CYLD-NRF2-OASL1 axis in stress-induced liver inflammation and cell death. JHEP reports : innovation in hepatology 59 36035360
1996 The cylindromatosis gene (cyld1) on chromosome 16q may be the only tumour suppressor gene involved in the development of cylindromas. Oncogene 57 8649842
2020 The long noncoding RNA CRAL reverses cisplatin resistance via the miR-505/CYLD/AKT axis in human gastric cancer cells. RNA biology 53 31885317
2019 LncRNA GMDS-AS1 inhibits lung adenocarcinoma development by regulating miR-96-5p/CYLD signaling. Cancer medicine 52 31860169
2015 Deubiquitinating enzyme CYLD mediates pressure overload-induced cardiac maladaptive remodeling and dysfunction via downregulating Nrf2. Journal of molecular and cellular cardiology 52 25935309
2016 The tumour suppressor CYLD regulates the p53 DNA damage response. Nature communications 50 27561390
2015 Hematopoietic stem cell quiescence and function are controlled by the CYLD-TRAF2-p38MAPK pathway. The Journal of experimental medicine 47 25824820
2007 Cylindromatosis and the CYLD gene: new lessons on the molecular principles of epithelial growth control. BioEssays : news and reviews in molecular, cellular and developmental biology 47 18008375
2024 CYLD regulates cell ferroptosis through Hippo/YAP signaling in prostate cancer progression. Cell death & disease 45 38246916
2016 Loss of CYLD expression unleashes Wnt signaling in multiple myeloma and is associated with aggressive disease. Oncogene 43 27775078
2002 Spiradenocylindroma of the kidney: clinical and genetic findings suggesting a role of somatic mutation of the CYLD1 gene in the oncogenesis of an unusual renal neoplasm. The American journal of surgical pathology 43 11756779
2011 CYLD regulates keratinocyte differentiation and skin cancer progression in humans. Cell death & disease 40 21900959
2011 CYLD inhibits tumorigenesis and metastasis by blocking JNK/AP1 signaling at multiple levels. Cancer prevention research (Philadelphia, Pa.) 39 21478324
2015 Phenotype-genotype correlations for clinical variants caused by CYLD mutations. European journal of medical genetics 38 25782638
2019 Loss of Tumor Suppressor CYLD Expression Triggers Cisplatin Resistance in Oral Squamous Cell Carcinoma. International journal of molecular sciences 37 31635163
2015 MiR-501-5p regulates CYLD expression and promotes cell proliferation in human hepatocellular carcinoma. Japanese journal of clinical oncology 37 25917358
2014 Cylindromatosis gene CYLD regulates hepatocyte growth factor expression in hepatic stellate cells through interaction with histone deacetylase 7. Hepatology (Baltimore, Md.) 37 24811579
2018 MicroRNA-301b promotes cell proliferation and apoptosis resistance in triple-negative breast cancer by targeting CYLD. BMB reports 35 30269739
2017 MiR-767 promoted cell proliferation in human melanoma by suppressing CYLD expression. Gene 35 29054757
2010 Rare occurrence of biallelic CYLD gene mutations in classical Hodgkin lymphoma. Genes, chromosomes & cancer 35 20607853
2023 CYLD in health and disease. Disease models & mechanisms 34 37387450
2015 MiR-454 prompts cell proliferation of human colorectal cancer cells by repressing CYLD expression. Asian Pacific journal of cancer prevention : APJCP 34 25824771
2014 Deubiquitinating activity of CYLD is impaired by SUMOylation in neuroblastoma cells. Oncogene 33 24909169
2021 Regulation of CYLD activity and specificity by phosphorylation and ubiquitin-binding CAP-Gly domains. Cell reports 32 34610306
2016 CYLD - a deubiquitylase that acts to fine-tune microtubule properties and functions. Journal of cell science 32 27173491
2014 The LEF1/CYLD axis and cIAPs regulate RIP1 deubiquitination and trigger apoptosis in selenite-treated colorectal cancer cells. Cell death & disease 32 24577083
2022 CYLD deficiency enhances metabolic reprogramming and tumor progression in nasopharyngeal carcinoma via PFKFB3. Cancer letters 31 35131382
2014 CYLD coordinates with EB1 to regulate microtubule dynamics and cell migration. Cell cycle (Georgetown, Tex.) 31 24552808
2022 The SPATA2/CYLD pathway contributes to doxorubicin-induced cardiomyocyte ferroptosis via enhancing ferritinophagy. Chemico-biological interactions 30 36195186
2016 The cylindromatosis (CYLD) gene and head and neck tumorigenesis. Cancers of the head & neck 30 31093340
2019 CYLD Regulates Centriolar Satellites Proteostasis by Counteracting the E3 Ligase MIB1. Cell reports 29 31067453
2019 Subquinocin, a small molecule inhibitor of CYLD and USP-family deubiquitinating enzymes, promotes NF-κB signaling. Biochemical and biophysical research communications 29 31898971
2018 Loss of CYLD promotes cell invasion via ALK5 stabilization in oral squamous cell carcinoma. The Journal of pathology 29 29235674
2020 CYLD Alterations in the Tumorigenesis and Progression of Human Papillomavirus-Associated Head and Neck Cancers. Molecular cancer research : MCR 26 32883697
2018 Epigenetic alterations of CYLD promoter modulate its expression in gastric adenocarcinoma: A footprint of infections. Journal of cellular physiology 26 30132887
2014 The cylindromatosis gene product, CYLD, interacts with MIB2 to regulate notch signalling. Oncotarget 26 25565632
2021 CYLD destabilizes NoxO1 protein by promoting ubiquitination and regulates prostate cancer progression. Cancer letters 25 34742871
2020 CYLD exaggerates pressure overload-induced cardiomyopathy via suppressing autolysosome efflux in cardiomyocytes. Journal of molecular and cellular cardiology 25 32553594
2014 Tumor suppressor cylindromatosis (CYLD) controls HIV transcription in an NF-κB-dependent manner. Journal of virology 25 24760882
2016 Receptor-Interacting Protein Kinase-2 Inhibition by CYLD Impairs Antibacterial Immune Responses in Macrophages. Frontiers in immunology 23 26834734
1999 A new hereditary cylindromatosis family associated with CYLD1 on chromosome 16. Human genetics 23 10480375
2022 CYLD deubiquitinates plakoglobin to promote Cx43 membrane targeting and gap junction assembly in the heart. Cell reports 22 36577382
2020 Reversal of CYLD phosphorylation as a novel therapeutic approach for adult T-cell leukemia/lymphoma (ATLL). Cell death & disease 22 32024820
2019 CYLD deficiency exacerbates lipopolysaccharide (LPS)-induced pyroptosis in astrocytes of mice with sepsis. Biochemical and biophysical research communications 21 31097224
2023 MALT1-dependent cleavage of CYLD promotes NF-κB signaling and growth of aggressive B-cell receptor-dependent lymphomas. Blood cancer journal 20 36922488
2019 MicroRNA-130a has pro-fibroproliferative potential in hypertrophic scar by targeting CYLD. Archives of biochemistry and biophysics 20 31283910
2016 CYLD Promotes TNF-α-Induced Cell Necrosis Mediated by RIP-1 in Human Lung Cancer Cells. Mediators of inflammation 20 27738385
2015 The deubiquitinating enzyme CYLD regulates the differentiation and maturation of thymic medullary epithelial cells. Immunology and cell biology 20 25601276
2022 Oxidative stress-induced lncRNA CYLD-AS1 promotes RPE inflammation via Nrf2/miR-134-5p/NF-κB signaling pathway. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 19 36165267
2021 Genetic Testing in CYLD Cutaneous Syndrome: An Update. The application of clinical genetics 19 34744449
2014 SCFβ-TRCP regulates osteoclastogenesis via promoting CYLD ubiquitination. Oncotarget 19 24961988
2012 A20 and CYLD do not share significant overlapping functions during B cell development and activation. Journal of immunology (Baltimore, Md. : 1950) 19 23002441
2010 Expression of CYLD and NF-kappaB in human cholesteatoma epithelium. Mediators of inflammation 19 20414373
2011 Serum response factor controls CYLD expression via MAPK signaling pathway. PloS one 18 21573132
2020 Downregulation of CYLD promotes IFN-γ mediated PD-L1 expression in thymic epithelial tumors. Lung cancer (Amsterdam, Netherlands) 17 32738418
2021 Stabilization of p18 by deubiquitylase CYLD is pivotal for cell cycle progression and viral replication. NPJ precision oncology 16 33654169
2021 Immune dysregulation in SHARPIN-deficient mice is dependent on CYLD-mediated cell death. Proceedings of the National Academy of Sciences of the United States of America 16 34887354
2018 Targeting Tropomyosin Receptor Kinase in Cutaneous CYLD Defective Tumors With Pegcantratinib: The TRAC Randomized Clinical Trial. JAMA dermatology 16 29955768
2013 PKCθ/β and CYLD are antagonistic partners in the NFκB and NFAT transactivation pathways in primary mouse CD3+ T lymphocytes. PloS one 16 23335970
2021 CYLD mediates human pulmonary artery smooth muscle cell dysfunction in congenital heart disease-associated pulmonary arterial hypertension. Journal of cellular physiology 15 33507567
2018 CYLD deficiency promotes pancreatic cancer development by causing mitotic defects. Journal of cellular physiology 15 30362575
2017 miR-922 regulates CYLD expression and promotes the cell proliferation of human hepatocellular carcinoma. Oncology reports 15 28184924
2016 Regulation of Oral Squamous Cell Carcinoma Proliferation Through Crosstalk Between SMAD7 and CYLD. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 15 26982322
2007 CYLD: a multifunctional deubiquitinase. Fly 15 18820455
2019 Tumor suppressor protein CYLD regulates morphogenesis of dendrites and spines. The European journal of neuroscience 14 31001844
2016 miR-186 suppressed CYLD expression and promoted cell proliferation in human melanoma. Oncology letters 14 27698793

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