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Showing RNF31 — HOIP is a alias.

RNF31

E3 ubiquitin-protein ligase RNF31 · UniProt Q96EP0

Length
1072 aa
Mass
119.7 kDa
Annotated
2026-06-10
100 papers in source corpus 35 papers cited in narrative 35 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

RNF31 (HOIP) is the catalytically active RING-IBR-RING (RBR) E3 ubiquitin ligase subunit of the LUBAC complex and is the central node generating linear (Met1-linked) ubiquitin chains that drive NF-κB-dependent survival signaling (PMID:22863777). It builds linear chains through a two-step RBR mechanism in which ubiquitin is transferred from an E2 onto the RING2 active-site cysteine to form a HECT-like thioester, after which a unique C-terminal Linear ubiquitin chain Determining Domain (LDD) orients the acceptor ubiquitin for nucleophilic attack on its N-terminus (PMID:22863777); structural studies of the apo, ubiquitin-bound, and E2~ubiquitin transfer-complex states defined how donor and acceptor ubiquitin are simultaneously coordinated and how active HOIP departs from the auto-inhibited RBR conformation to align catalytic centers (PMID:24141947, PMID:26789245). Through linear ubiquitination of substrates such as NEMO and FADD, HOIP controls NF-κB activation downstream of multiple receptors including CD40, TNFR2, and STING (PMID:28189684, PMID:21829693, PMID:29378181, PMID:39578541), and its activity is essential to protect cells from cytokine-induced death: catalytic-dead or tissue-specific HOIP loss sensitizes endothelial cells, keratinocytes, and T cells to TNF-driven apoptosis/necroptosis, phenotypes rescued by TNFR1 deletion (PMID:25284787, PMID:29728512, PMID:27786304). HOIP activity is itself tuned by deubiquitinase recruitment via direct PUB-domain binding to OTULIN (PMID:24726327) and SPATA2-bridged engagement of CYLD (PMID:27545878), by caspase cleavage at Asp348/387/390 during apoptosis (PMID:28189684, PMID:27669734), and by auto-ubiquitination at Lys1056 that confers TLR4-specific conformational inhibition (PMID:26578682). Beyond canonical LUBAC substrates, HOIP attaches non-degradative and degradative ubiquitin marks to a range of targets, stabilizing GPx4 to suppress ferroptosis (PMID:36279464) and NLRP3 via K63 chains (PMID:37951199) while driving K48-linked degradation of A20, PTEN, YAP, and p53 (PMID:34416243, PMID:34659546, PMID:36581998, PMID:33824292). Loss or pharmacologic inhibition of RNF31 sensitizes tumor cells to TNF-dependent killing by NK and CD8+ T cells, establishing it as a target for immune-mediated cancer therapy (PMID:35688159, PMID:35379808, PMID:34467615). A hypomorphic PUB-domain mutation (L72P) destabilizes LUBAC and causes defective linear ubiquitination and immunodeficiency in patients (PMID:26008899).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2004 Low

    An initial question was whether RNF31 had any defined molecular partner; identifying it as an Ariadne-like RBR protein binding the MuSK cytoplasmic domain gave the first functional context, though unrelated to its later-established LUBAC role.

    Evidence Yeast two-hybrid/binding assay and NMJ localization by in situ hybridization and immunostaining

    PMID:14678832

    Open questions at the time
    • Single binding assay with no functional validation of the MuSK interaction
    • No connection drawn to ubiquitin ligase activity or NF-κB signaling
    • Not reconciled with the canonical LUBAC function
  2. 2009 Medium

    Before its NF-κB role was defined, RNF31 was found to act as a transcriptional corepressor, establishing an early link between RNF31 and ubiquitin-dependent stabilization of a partner protein.

    Evidence Co-IP, ChIP, siRNA knockdown and reporter/ubiquitination assays on steroidogenic gene promoters with DAX-1

    PMID:19237537

    Open questions at the time
    • Ubiquitin linkage type on DAX-1 not defined
    • Mechanism connecting stabilization to repression unresolved
    • Relationship to LUBAC complex unaddressed
  3. 2011 Medium

    To determine which receptors require HOIP, studies showed it is recruited TRAF2-dependently to the CD40 complex and is essential for CD40-driven NF-κB, establishing HOIP catalytic activity as required for proximal receptor signaling.

    Evidence Mass spectrometry of CD40 complexes, HOIP KO B-cell lines, dominant-negative catalytic mutant, NF-κB/kinase assays

    PMID:20614026 PMID:21829693

    Open questions at the time
    • Direct CD40-complex substrate of HOIP not identified
    • Linear chain linkage at CD40 complex not directly demonstrated
  4. 2012 High

    The defining mechanistic question — how HOIP generates linear chains — was answered by showing a two-step RBR mechanism with a HECT-like thioester intermediate and an LDD that confers linear specificity.

    Evidence In vitro ubiquitination assays, active-site mutagenesis, cellular NF-κB reporter assays

    PMID:22863777

    Open questions at the time
    • Atomic basis of acceptor orientation not yet visualized
    • Priming versus extension steps not distinguished
  5. 2016 High

    Structural studies progressively explained linear chain specificity and catalysis, capturing donor- and acceptor-ubiquitin coordination and the active transfer conformation distinct from auto-inhibited RBRs.

    Evidence X-ray crystallography of apo, ubiquitin-bound, and HOIP RBR/E2~ubiquitin transfer complexes with mutagenesis

    PMID:24141947 PMID:26789245

    Open questions at the time
    • Full-length LUBAC architecture not resolved
    • Conformational transition kinetics not measured
  6. 2016 High

    How HOIP activity is restrained was addressed by defining deubiquitinase recruitment: direct PUB-domain binding to OTULIN (regulated by OTULIN Tyr56 phosphorylation) and SPATA2-bridged CYLD recruitment.

    Evidence Structural determination of the PUB-PIM interface, phospho-mimetic mutagenesis, reciprocal Co-IP, receptor-complex pull-down, SPATA2 KO necroptosis assays

    PMID:24726327 PMID:27545878

    Open questions at the time
    • Quantitative balance between OTULIN and CYLD restraint unresolved
    • How phosphorylation is triggered in vivo not defined
  7. 2018 High

    Genetic models established the physiological imperative for HOIP catalytic activity in preventing cytokine-induced death across endothelium, epidermis, and T cells, with TNFR1 epistasis defining the death ligand.

    Evidence Constitutive, Tie2-Cre, epidermis-specific conditional KO and catalytic knock-in mice with TNFR1-KO genetic rescue and CD127 rescue

    PMID:25284787 PMID:27786304 PMID:29728512

    Open questions at the time
    • The specific substrate whose linear ubiquitination prevents complex-II death not fully resolved per tissue
    • Necroptosis versus apoptosis contributions vary by context
  8. 2018 Medium

    Receptor scope was extended by showing cIAP1-dependent HOIP recruitment to the TNFR2 complex, broadening the set of NF-κB pathways routed through linear ubiquitination.

    Evidence TNFR2 complex IP, cIAP antagonist treatment, M1/K63 linkage-specific blotting, NF-κB assays

    PMID:29378181

    Open questions at the time
    • TNFR2-complex substrate of M1 chains not identified
    • Single study
  9. 2017 Medium

    How HOIP is switched off during apoptosis and which pathway-specific regulation it undergoes were addressed by mapping caspase cleavage sites, the K1056 auto-ubiquitination switch, and identifying FADD as a linear ubiquitination substrate.

    Evidence Caspase cleavage and site mutagenesis, K1056R mutagenesis, in vitro ubiquitination and NF-κB/apoptosis assays, NEMO/FADD linear ubiquitination assays

    PMID:26578682 PMID:27669734 PMID:28189684

    Open questions at the time
    • Physiological trigger of K1056 auto-ubiquitination in TLR4 signaling not defined
    • Fate of cleavage fragments in vivo unclear
  10. 2020 Medium

    Reconstitution chemistry refined the catalytic model by separating NEMO linear ubiquitylation into a priming event requiring factors beyond HOIP and a HOIP RBR-mediated extension step.

    Evidence Chemical ubiquitylation of NEMO, in vitro extension with HOIP RBR domain, ITC binding measurements

    PMID:31942456

    Open questions at the time
    • Identity of the priming factor not established
    • Single-lab in vitro reconstitution
  11. 2024 Medium

    The repertoire of HOIP substrates and pathways was expanded substantially, revealing both linear (GPx4, STING-associated) and non-canonical chain functions (NLRP3 K63 stabilization; K48 degradation of A20, PTEN, YAP, p53; ERα/DAX-1 stabilization; ALYREF nuclear transport).

    Evidence Co-IP, linkage-specific and site-directed ubiquitination assays, knockdown/inhibitor rescue, in vivo disease and organoid models across ferroptosis, inflammasome, liver injury, mitophagy and chemoresistance

    PMID:24441041 PMID:33824292 PMID:34416243 PMID:34659546 PMID:36279464 PMID:36581998 PMID:37951199 PMID:38615890 PMID:39578541 PMID:39915011

    Open questions at the time
    • Most non-canonical substrates rest on single-lab Co-IP plus ubiquitination assays
    • Chain linkage and direct-versus-indirect ubiquitination not uniformly confirmed
    • Reconciliation of degradative versus stabilizing roles per substrate incomplete
  12. 2022 High

    The translational question of whether HOIP can be exploited therapeutically was answered by structure-based covalent inhibitors and by CRISPR/pharmacologic studies showing RNF31 ablation sensitizes tumors to TNF-dependent immune killing.

    Evidence Fragment-based covalent inhibitor crystallography and chemoproteomics; genome-wide CRISPR screens under NK/CD8+ T cell pressure, inhibitor treatment, organoid and orthotopic tumor models

    PMID:30657686 PMID:34467615 PMID:35379808 PMID:35688159

    Open questions at the time
    • In vivo selectivity and off-target effects of inhibitors not fully defined
    • Patient-level efficacy untested in the corpus

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how HOIP selects among its many reported substrates and switches between generating linear, K48, and K63 linkages on different targets, and which priming factors and contextual cues dictate these outcomes in vivo.
  • No unifying mechanism explains linkage-type switching across substrates
  • NEMO priming factor unidentified
  • Many non-canonical substrate claims await independent validation

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0016874 ligase activity 3 GO:0003723 RNA binding 1
Localization
GO:0005634 nucleus 2 GO:0005794 Golgi apparatus 1 GO:0005829 cytosol 1
Pathway
R-HSA-392499 Metabolism of proteins 5 R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 4 R-HSA-5357801 Programmed Cell Death 4
Partners
A20CYLDNLRP3OTULINRBCK1SPATA2TRAF2YAP
Complex memberships
LUBAC

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 HOIP (RNF31) is the catalytically active subunit of LUBAC and generates linear (Met1-linked) ubiquitin chains via a two-step RBR mechanism: RING1-IBR catalyzes transfer of ubiquitin from E2 onto RING2 to form a transient HECT-like thioester intermediate, after which ubiquitin is transferred to the N-terminus of an acceptor ubiquitin. A unique C-terminal region termed the Linear ubiquitin chain Determining Domain (LDD) coordinates the acceptor ubiquitin and confers specificity for linear chain formation. In vitro ubiquitination assays, active-site mutagenesis, cellular NF-κB reporter assays The EMBO journal High 22863777
2013 Crystal structure of the catalytic core of HOIP in apo form and in complex with ubiquitin revealed a novel C-terminal fold that, together with a zinc-finger, forms a ubiquitin-binding platform orienting the acceptor ubiquitin for nucleophilic attack on the E3~ubiquitin thioester. The structure captured both donor and acceptor ubiquitin simultaneously, explaining determinants of linear chain specificity. Mutations in these interfaces impair NF-κB pathway activation in vivo. X-ray crystallography (apo and ubiquitin-bound), mutagenesis, NF-κB activation assays Nature High 24141947
2016 Crystal structure of fully active HOIP RBR in complex with an E2~ubiquitin conjugate revealed that active HOIP adopts a conformation markedly different from auto-inhibited RBRs, binds the E2~ubiquitin conjugate in an elongated fashion with catalytic centres aligned for HECT-like ubiquitin transfer, and contains three helix-IBR-fold motifs that bind both the activated (donor) ubiquitin and an additional regulatory ubiquitin molecule. X-ray crystallography of HOIP RBR/E2~ubiquitin transfer complex, structural comparison with Parkin and HHARI Nature High 26789245
2014 The HOIP PUB domain directly binds the PUB-interacting motif (PIM) of the deubiquitinase OTULIN; structural studies defined the binding interface with OTULIN Tyr56 making critical contacts. Phosphorylation of OTULIN Tyr56 negatively regulates this interaction. HOIP–OTULIN interaction is required for recruitment of OTULIN to the TNF receptor complex and to counteract HOIP-dependent NF-κB activation. Structural studies (X-ray/NMR), co-immunoprecipitation, phospho-mimetic mutagenesis, TNF receptor complex pull-down assays Molecular cell High 24726327
2016 SPATA2 is a constitutive direct binding partner of HOIP that bridges the interaction between the deubiquitinase CYLD and HOIP. Recruitment of SPATA2 to TNFR1 and NOD2 signaling complexes is HOIP-dependent; loss of SPATA2 abolishes CYLD recruitment and reduces TNF-induced necroptosis. Co-immunoprecipitation, signaling complex pull-down, SPATA2 knockout cell lines, necroptosis assays Cell reports High 27545878
2014 HOIP (RNF31) associates with estrogen receptor α (ERα) predominantly in the cytosol, increases ERα stability and mono-ubiquitination in an E3-ligase-activity-dependent manner, and is required for ERα-stimulated breast cancer cell proliferation and downstream target gene expression (cyclin D1, c-myc). RNF31 depletion reduces S-phase entry and ERα protein levels. Co-immunoprecipitation, RNF31 siRNA knockdown, cycloheximide-chase stability assay, cell-cycle analysis (FACS), luciferase reporter assays Oncogene Medium 24441041
2009 RNF31 forms an in vivo corepressor complex with DAX-1 at the promoters of steroidogenic genes StAR and CYP19, stabilizes DAX-1 (linked to DAX-1 mono-ubiquitination), and is required for DAX-1-mediated repression of steroidogenic gene transcription. Co-immunoprecipitation, chromatin immunoprecipitation (ChIP), RNF31 siRNA knockdown, reporter assays, ubiquitination assays Molecular and cellular biology Medium 19237537
2011 HOIP (RNF31) is recruited to the CD40 signaling complex in a TRAF2-dependent manner and is essential for CD40-mediated NF-κB activation; a ubiquitin-ligase-dead HOIP mutant inhibits NF-κB, and HOIP-deficient B cells fail to activate NF-κB, c-Jun kinase, or recruit IKK proteins to the CD40 complex. Somatic gene targeting (HOIP KO B cell lines), dominant-negative mutant overexpression, Co-IP/signaling complex analysis, NF-κB reporter and kinase assays PloS one Medium 21829693
2010 HOIP/RNF31 is recruited to the CD40 signaling complex in a TRAF2-dependent manner (identified by mass spectrometry of immunoprecipitated CD40 complexes); a catalytically inactive HOIP mutant inhibits CD40-mediated NF-κB activation, indicating that HOIP ubiquitin-ligase activity is required for proximal CD40 signaling. Stimulation/immunoprecipitation of CD40 complexes + mass spectrometry, dominant-negative HOIP mutant, NF-κB reporter assay PloS one Medium 20614026
2014 HOIP is required to prevent TNF-induced cell death in endothelial cells during embryogenesis; its catalytic activity is necessary for this protective function. HOIP-deficient cells show aberrant TNFR1 complex-II formation and are hypersensitive to TNF and LTα-induced death. TNFR1 deletion rescues embryonic lethality of HOIP-null mice. Constitutive and Tie2-Cre conditional HOIP knockout mice, apoptosis assays, TNFR1 genetic rescue (double-KO), signaling complex analysis Cell reports High 25284787
2015 A hypomorphic missense mutation (L72P) in the HOIP PUB domain impairs HOIP protein expression and destabilizes the entire LUBAC complex, causing defective linear ubiquitination and NF-κB activation in response to IL-1β and TNF in patient fibroblasts, and impaired B-cell activation in response to CD40 engagement. Patient primary cell analysis, western blot for LUBAC complex integrity, NF-κB activation assays, B-cell functional assays The Journal of experimental medicine Medium 26008899
2017 HOIP is cleaved by caspases predominantly at Asp390 during apoptosis and is subsequently degraded by the proteasome. Effector caspases 3 and 6 cleave at aspartates 348, 387, and 390. The N-terminal cleavage fragment retains binding to OTULIN and CYLD-SPATA2; the C-terminal fragment retains NF-κB activity, but overall linear ubiquitination of NEMO and FADD (both identified as LUBAC substrates) decreases upon apoptosis. FADD is identified as a novel substrate for linear ubiquitination by LUBAC. Caspase cleavage assays, site-directed mutagenesis of cleavage sites, western blot, NF-κB reporter assays, linear ubiquitination assays for NEMO and FADD Biochemical and biophysical research communications Medium 28189684
2016 RNF31/HOIP is cleaved by caspases 3 and 6 at aspartates 348, 387, and 390 under apoptotic conditions, and this cleavage suppresses its ability to activate NF-κB signaling. Mutation of caspase cleavage sites inhibits TNF-α-induced apoptosis, establishing a regulatory loop between cell death and survival signaling. In vitro caspase cleavage assays, site-directed mutagenesis, apoptosis assays, NF-κB reporter assays Molecular and cellular biology Medium 27669734
2015 Ubiquitination of HOIP at C-terminal lysine 1056 negatively regulates its catalytic activity by inducing a conformational change that suppresses linear-chain-forming activity. HOIP K1056R mutation leads to persistent LUBAC activity and prolonged NF-κB activation induced by TLR4/LPS stimulation but not by CD40 stimulation, indicating pathway-specific regulation. Site-directed mutagenesis (K1056R), in vitro ubiquitination assays, NF-κB reporter assays, TLR4 signaling experiments mBio Medium 26578682
2018 HOIP (as LUBAC component) is recruited to the TNFR2 signaling complex in a cIAP1-dependent manner; loss of cIAP1 (via cIAP antagonist) prevents HOIP recruitment and HOIP-mediated M1-ubiquitination at the TNFR2 complex. Both HOIP and cIAP1 are required for TNFR2-induced canonical NF-κB activation. TNFR2 signaling complex immunoprecipitation, cIAP antagonist treatment, M1/K63 ubiquitin linkage-specific antibody blotting, NF-κB activation assays Biochemical pharmacology Medium 29378181
2018 Epidermis-specific knockout of RNF31 in mice causes early postnatal lethality with severe skin inflammation driven by TNF-α-induced apoptosis in keratinocytes. RNF31 deficiency impairs TNF-α-induced NF-κB activation and increases apoptosis. Genetic deletion of TNFR1 rescues lethality and skin inflammation in RNF31 epidermis-KO mice. Epidermis-specific conditional KO mice, genetic epistasis (TNFR1 KO rescue), apoptosis assays, NF-κB activation assays Journal of immunology High 29728512
2016 In T cell-specific HOIP-knockin mice expressing a catalytically inactive HOIP (HOIPΔlinear), CD4+ and CD8+ T cell numbers are markedly reduced, NKT cell development is severely impaired, and mature T cells undergo accelerated apoptosis. HOIPΔlinear CD4+ T cells fail to phosphorylate IκBα and JNK through TCR stimulation. Reduced CD127 expression contributes to apoptosis; enforced CD127 expression rescues mature CD8+ T cell development. Conditional knock-in mice with catalytically inactive HOIP, flow cytometry, TCR signaling (phospho-IκBα, phospho-JNK), apoptosis assays, CD127 rescue experiment Scientific reports High 27786304
2022 LUBAC/HOIP binds GPx4 and stabilizes it by modulating its linear ubiquitination, protecting cells against ferroptosis. LUBAC deficiency sensitizes cells to ferroptosis by promoting GPx4 degradation and downstream lipid peroxidation. GPx4 is identified as a direct substrate of HOIP-mediated linear ubiquitination. Co-immunoprecipitation, linear ubiquitination assays, lipid peroxidation assays, ferroptosis sensitivity assays in LUBAC-deficient cells Proceedings of the National Academy of Sciences of the United States of America Medium 36279464
2022 RNF31 genetic or pharmacologic ablation sensitizes cancer cells to NK cell and CD8+ T cell killing in a TNF-dependent manner, causing loss of A20 and non-canonical IKK complexes from TNF receptor complex I. A small-molecule RNF31 inhibitor sensitizes colon carcinoma organoids to TNF and enhances bystander killing of MHC-deficient tumor cells. Genome-wide CRISPR-Cas9 knockout screens under NK/CD8+ T cell pressure, pharmacological RNF31 inhibitor, TNF receptor complex analysis, tumor organoid killing assays Cell reports. Medicine High 35688159
2022 Loss of Rnf31 in pancreatic cancer cells removes protection from TNF-mediated caspase-8 cleavage and subsequent apoptosis, sensitizing tumor cells to CD8+ T cell killing. Rnf31-deficient orthotopic pancreatic tumors show increased CD8+ T cell infiltration and effector function in vivo. In vitro and in vivo CRISPR screening, caspase-8 cleavage assays, orthotopic transplantation into immune-competent mice, T cell functional assays, human PDA organoids Nature communications High 35379808
2021 HOIP-deficient melanoma cells are hypersensitive to combined TNF and IFN-γ killing by NK and CD8+ T cells. Both genetic deletion and pharmacological inhibition of HOIP increase tumor cell sensitivity to TNF+IFN-γ co-stimulation, which engages both intrinsic and extrinsic apoptotic machinery in a transcription-dependent manner. CRISPR/Cas9 HOIP KO, pharmacological HOIP inhibition, NK/CD8+ T cell co-culture killing assays, cytokine treatment experiments, apoptosis pathway analysis EMBO reports Medium 34467615
2021 RNF31 interacts with A20 via its RBR structural domain (co-immunoprecipitation), promotes K48-linked ubiquitination of A20 and its proteasomal degradation, thereby activating the TLR4/MyD88/NF-κB signaling pathway and aggravating hepatocyte apoptosis and inflammatory cytokine production. Co-immunoprecipitation, ubiquitination assays, proteasome inhibitor experiments (actinomycin chase + MG132), siRNA knockdown, in vivo LPS/d-Gal acute liver injury model Chemico-biological interactions Medium 34416243
2021 RNF31/HOIP associates with PTEN via co-immunoprecipitation and promotes PTEN ubiquitination and proteasomal degradation in cancer cells. HOIP depletion causes cell cycle arrest and apoptosis that can be rescued by PTEN silencing, implicating a HOIP–PTEN–PI3K/AKT axis in chemotherapy resistance. Co-immunoprecipitation, ubiquitination assays, PTEN knockdown rescue, cell cycle analysis, apoptosis assays Journal of Cancer Medium 34659546
2021 RNF31 interacts with NLRP3 via its RBR domain and promotes K63-linked ubiquitination of NLRP3, stabilizing the NLRP3 inflammasome complex and enhancing IL-1β and IL-18 production. In vivo RNF31 knockdown attenuates DSS-induced colitis and reduces NLRP3 expression. Co-immunoprecipitation, ubiquitination assays (K63-linkage specific), RNF31 KD cell model, DSS-induced colitis mouse model International immunopharmacology Medium 37951199
2022 RBCK1 (HOIL-1L) interacts with RNF31 and represses RNF31 ubiquitination and proteasomal degradation, thereby stabilizing RNF31 protein in hepatocellular carcinoma cells. Co-immunoprecipitation, ubiquitination assays, proteasome inhibitor experiments, RNF31/RBCK1 KD cell lines Cell death discovery Medium 35869046
2022 RNF31 depletion in TNBC increases YAP protein levels; RNF31 associates with YAP, facilitates YAP poly-ubiquitination and proteasomal degradation specifically at YAP K76, and suppresses Hippo/YAP/PD-L1 axis, thereby repressing TNBC cell proliferation, migration, and immune checkpoint expression. Co-immunoprecipitation, ubiquitination assays, site-directed mutagenesis (YAP K76), xenograft models, genome-wide expression profiling, siRNA KD Journal of experimental & clinical cancer research Medium 36581998
2021 RNF31 interacts with p53 via its PUB domain (demonstrated by truncation Co-IP assays), promotes p53 ubiquitination and proteasomal degradation, and the PUB domain is the key structural determinant for p53 ubiquitination. RNF31 depletion stabilizes p53 and inhibits CRC cell growth. Co-immunoprecipitation with truncation constructs, cycloheximide-chase assay, MG132 proteasome inhibition, ubiquitination assays Cell death discovery Medium 33824292
2024 RNF31 enhances p53 ubiquitination and proteasomal degradation; reduced RNF31 leads to p53 accumulation, which represses BNIP3 expression, impairing mitophagy and promoting steatosis in hepatocytes. RNF31 delivery via mesenchymal stem cell-derived small extracellular vesicles reduces hepatic steatosis in HFD-fed mice. Co-immunoprecipitation, ubiquitination assays, mt-Keima fluorescence mitophagy assay, RNA-seq, HFD mouse model, sEV delivery experiments Free radical biology & medicine Medium 38615890
2024 STING activation induces recruitment of HOIP (LUBAC) to LC3B-associated Golgi membranes and synthesis of M1-linked (linear) ubiquitin chains. Loss of HOIP prevents M1-Ub chain formation and reduces STING-induced NF-κB and IRF3 signaling in human THP1 monocytes and mouse bone marrow-derived macrophages, without affecting upstream STING activation itself. HOIP KO in THP1 monocytes and BMDMs, M1-Ub chain detection, STING pathway signaling assays (IRF3/NF-κB), LC3B/Golgi co-localization imaging The EMBO journal Medium 39578541
2019 Fragment-based covalent ligand screening targeting the active-site cysteine of HOIP yielded the first structure-based covalent inhibitors for an RBR E3 ligase. Crystal structures of HOIP-inhibitor complexes were solved; cell-based and chemoproteomic assays confirmed cell-penetrant HOIP labeling and inhibition of NF-κB activation. Fragment covalent screening, protein LC-MS ubiquitination assays, protein crystallography, cell-based NF-κB reporter assays, chemoproteomics Journal of the American Chemical Society High 30657686
2014 HOIP (RNF31) is identified by siRNA screen as a key regulator of cisplatin-induced genotoxicity; HOIP-deficient cells exhibit hypersensitivity to cisplatin via increased caspase-8/caspase-3-dependent apoptosis that requires ATM (not ATR) checkpoint activation. JNK activity is enhanced in HOIP-depleted cells and JNK inhibition reverses apoptotic hyperactivation. siRNA library screen, caspase activity assays, ATM/ATR pathway inhibitors, JNK inhibition rescue, cisplatin-resistance assays Cancer research Medium 24686174
2021 DC-specific deletion of HOIP causes spontaneous inflammation; HOIP deficiency in DCs does not affect TNF-α-induced NF-κB activation but enhances TNF-α-induced apoptosis and necroptosis. Crossing with TNFR1-KO does not rescue inflammation, whereas antibiotic treatment reduces it. MyD88 deficiency rescues the inflammatory phenotype in HOIP-deficient DC mice, establishing MyD88-dependent (TLR) signaling—not TNFR1 signaling—as the driver of autoinflammation. DC-specific conditional HOIP KO mice, genetic epistasis (TNFR1-KO, MyD88-KO crosses), antibiotic treatment, apoptosis/necroptosis assays, cytokine measurement Journal of immunology High 34253576
2019 Chemical ubiquitylation of NEMO using a ligation auxiliary demonstrated that monoubiquitylated NEMO retains similar affinity for linear diubiquitin chains as unmodified NEMO. The proximal ubiquitin of chemically synthesized NEMO-Ub is accepted as substrate for linear extension by the HOIP RBR domain alone, indicating NEMO linear ubiquitylation involves a two-step mechanism: an initial priming event (requiring factors beyond HOIP alone) and a separate HOIP RBR-mediated extension step. Chemical ubiquitylation (ligation auxiliary), in vitro linear extension assays with HOIP RBR domain, ITC binding affinity measurements Communications chemistry Medium 31942456
2025 RNF31 interacts with and ubiquitinates ALYREF (RNA export factor), facilitating ALYREF nuclear transport via importin 13 (IPO13) under paclitaxel treatment; nuclear ALYREF then mediates export of mRNAs encoding paclitaxel-resistance factors (TUBB3, STMN1, TAU), inducing resistance. RNF31 inhibition traps ALYREF in the cytoplasm and re-sensitizes resistant TNBC cells to paclitaxel. Co-immunoprecipitation, ubiquitination assays, immunofluorescence (ALYREF subcellular localization), mRNA export assays, siRNA KD, RNF31 inhibitor + paclitaxel in vivo and organoid models Clinical and translational medicine Medium 39915011
2004 RNF31/PAUL (identified as a putative Ariadne-like RBR E3 ubiquitin ligase) binds the cytoplasmic domain of the muscle-specific receptor tyrosine kinase MuSK and is expressed at neuromuscular junctions, suggesting a role in postsynaptic membrane formation. Yeast two-hybrid and binding assay identifying PAUL as MuSK-interacting protein, in situ hybridization and immunostaining for NMJ localization Gene expression patterns Low 14678832

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 HOIP deficiency causes embryonic lethality by aberrant TNFR1-mediated endothelial cell death. Cell reports 219 25284787
2015 Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia. The Journal of experimental medicine 217 26008899
2012 The E3 ligase HOIP specifies linear ubiquitin chain assembly through its RING-IBR-RING domain and the unique LDD extension. The EMBO journal 192 22863777
2013 Structural basis for ligase-specific conjugation of linear ubiquitin chains by HOIP. Nature 179 24141947
2014 Binding of OTULIN to the PUB domain of HOIP controls NF-κB signaling. Molecular cell 153 24726327
2016 Structure of a HOIP/E2~ubiquitin complex reveals RBR E3 ligase mechanism and regulation. Nature 152 26789245
2005 Results of spot-scanning proton radiation therapy for chordoma and chondrosarcoma of the skull base: the Paul Scherrer Institut experience. International journal of radiation oncology, biology, physics 150 16168833
2009 Our perception of the mast cell from Paul Ehrlich to now. European journal of immunology 140 19130582
2020 Mast cells as a unique hematopoietic lineage and cell system: From Paul Ehrlich's visions to precision medicine concepts. Theranostics 139 32929378
2016 SPATA2-Mediated Binding of CYLD to HOIP Enables CYLD Recruitment to Signaling Complexes. Cell reports 116 27545878
2019 Fragment-Based Covalent Ligand Screening Enables Rapid Discovery of Inhibitors for the RBR E3 Ubiquitin Ligase HOIP. Journal of the American Chemical Society 98 30657686
2014 The atypical ubiquitin ligase RNF31 stabilizes estrogen receptor α and modulates estrogen-stimulated breast cancer cell proliferation. Oncogene 82 24441041
2019 Second Case of HOIP Deficiency Expands Clinical Features and Defines Inflammatory Transcriptome Regulated by LUBAC. Frontiers in immunology 65 30936877
2014 E3 ubiquitin ligase HOIP attenuates apoptotic cell death induced by cisplatin. Cancer research 59 24686174
2013 Spot-scanning proton radiation therapy for pediatric chordoma and chondrosarcoma: clinical outcome of 26 patients treated at paul scherrer institute. International journal of radiation oncology, biology, physics 59 23582853
2018 Controlling Mast Cell Activation and Homeostasis: Work Influenced by Bill Paul That Continues Today. Frontiers in immunology 58 29755466
1997 The Paul Kallos Memorial Lecture. The mast cell: a versatile effector cell for a challenging world. International archives of allergy and immunology 55 9130474
2016 Magnetic nanoparticle-induced hyperthermia with appropriate payloads: Paul Ehrlich's "magic (nano)bullet" for cancer theranostics? Cancer treatment reviews 52 27756009
2022 HOIP modulates the stability of GPx4 by linear ubiquitination. Proceedings of the National Academy of Sciences of the United States of America 44 36279464
2022 RNF31 inhibition sensitizes tumors to bystander killing by innate and adaptive immune cells. Cell reports. Medicine 43 35688159
2022 Loss of Rnf31 and Vps4b sensitizes pancreatic cancer to T cell-mediated killing. Nature communications 41 35379808
2016 Timing and causes of mid-Holocene mammoth extinction on St. Paul Island, Alaska. Proceedings of the National Academy of Sciences of the United States of America 41 27482085
2009 E3 ubiquitin ligase RNF31 cooperates with DAX-1 in transcriptional repression of steroidogenesis. Molecular and cellular biology 39 19237537
1989 Dyes, antipsychotic drugs, and antimicrobial activity. Fragments of a development, with special reference to the influence of Paul Ehrlich. Danish medical bulletin 38 2651032
2016 Paul Ehrlich and the Early History of Granulocytes. Microbiology spectrum 36 27726791
2018 The E3 ubiquitin ligases HOIP and cIAP1 are recruited to the TNFR2 signaling complex and mediate TNFR2-induced canonical NF-κB signaling. Biochemical pharmacology 35 29378181
2006 Outcome following hepatic resection of metastatic renal tumors: the Paul Brousse Hospital experience. HPB : the official journal of the International Hepato Pancreato Biliary Association 34 18333255
2017 Decreased linear ubiquitination of NEMO and FADD on apoptosis with caspase-mediated cleavage of HOIP. Biochemical and biophysical research communications 32 28189684
2015 miR-503 suppresses tumor cell proliferation and metastasis by directly targeting RNF31 in prostate cancer. Biochemical and biophysical research communications 31 26231797
2011 HOIL-1L interacting protein (HOIP) is essential for CD40 signaling. PloS one 31 21829693
2013 Receptor-mediated endocytosis for drug delivery in African trypanosomes: fulfilling Paul Ehrlich's vision of chemotherapy. Trends in parasitology 30 23601931
1984 Aberrant expression of Forssman and Paul-Bunnell antigens on lymph node cells of MRL/Mp-lpr/lpr mice. Journal of immunology (Baltimore, Md. : 1950) 30 6333455
2021 HOIP limits anti-tumor immunity by protecting against combined TNF and IFN-gamma-induced apoptosis. EMBO reports 29 34467615
2016 Atypical ubiquitin ligase RNF31: the nuclear factor modulator in breast cancer progression. BMC cancer 29 27460922
2010 The endogenous peptides of normal human serum extracted from the acetonitrile-insoluble precipitate using modified aqueous buffer with analysis by LC-ESI-Paul ion trap and Qq-TOF. Journal of proteomics 29 20211283
2012 Knockdown of SF-1 and RNF31 affects components of steroidogenesis, TGFβ, and Wnt/β-catenin signaling in adrenocortical carcinoma cells. PloS one 28 22427816
2010 HOIL-1L interacting protein (HOIP) as an NF-kappaB regulating component of the CD40 signaling complex. PloS one 26 20614026
1996 Paul Ehrlich: pathfinder in cell biology. 1. Chronicle of his life and accomplishments in immunology, cancer research, and chemotherapy. Biotechnic & histochemistry : official publication of the Biological Stain Commission 26 9138526
1993 Computer simulation of single-ion trajectories in paul-type ion traps. Journal of the American Society for Mass Spectrometry 26 24225994
2022 RNF31 represses cell progression and immune evasion via YAP/PD-L1 suppression in triple negative breast Cancer. Journal of experimental & clinical cancer research : CR 25 36581998
2021 Taraxasterol acetate targets RNF31 to inhibit RNF31/p53 axis-driven cell proliferation in colorectal cancer. Cell death discovery 24 33824292
2011 The discovery of endothelium-dependent contraction: the legacy of Paul M. Vanhoutte. Pharmacological research 22 21385610
2009 Did Paul Kammerer discover epigenetic inheritance? A modern look at the controversial midwife toad experiments. Journal of experimental zoology. Part B, Molecular and developmental evolution 22 19731234
2008 Production and separation of ''non-standard'' PET nuclides at a large cyclotron facility: the experiences at the Paul Scherrer Institute in Switzerland. The quarterly journal of nuclear medicine and molecular imaging : official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR), [and] Section of the Society of... 22 18174878
2007 Forty years of antipsychotic Drug research--from haloperidol to paliperidone--with Dr. Paul Janssen. Arzneimittel-Forschung 22 18074755
1972 Polyphenol synthesis in cell suspension cultures of Paul's Scarlet rose. Planta 22 24481656
2012 Availability, brands, labelling and Salmonella contamination of raw pet food in the Minneapolis/St. Paul area. Zoonoses and public health 21 22551080
2004 Identification of the protein Zibra, its genomic organization, regulation, and expression in breast cancer cells. Experimental cell research 21 15093743
2022 From magic bullets to modern therapeutics: Paul Ehrlich, the German immunobiologist and physician coined the term 'complement'. Molecular immunology 20 36027818
2018 RNF31 Regulates Skin Homeostasis by Protecting Epidermal Keratinocytes from Cell Death. Journal of immunology (Baltimore, Md. : 1950) 20 29728512
2018 Hematological profile of pregnant women at St. Paul's Hospital Millennium Medical College, Addis Ababa, Ethiopia. BMC hematology 20 30002836
2008 Ilya Ilich Metchnikoff (1845-1915) and Paul Ehrlich (1854-1915): the centennial of the 1908 Nobel Prize in Physiology or Medicine. Journal of medical biography 20 18463079
1999 Paul Ehrlich's passion: the origins of his receptor immunology. Cellular immunology 20 10383824
1987 Expression of heterophile, Paul-Bunnell and Hanganutziu-Deicher antigens on human melanoma cell lines. International archives of allergy and applied immunology 20 3294601
2020 Evaluation of Peripheral Blood Parameters of Pulmonary Tuberculosis Patients at St. Paul's Hospital Millennium Medical College, Addis Ababa, Ethiopia: Comparative Study. Journal of blood medicine 19 32308514
2008 Cancer, viruses, and mass migration: Paul Berg's venture into eukaryotic biology and the advent of recombinant DNA research and technology, 1967-1980. Journal of the history of biology 19 19244843
1999 Retransplantation of the liver for recurrent hepatitis B virus infection: the Paul Brousse experience. Liver transplantation and surgery : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society 19 10226106
2006 Paul Ehrlich's "Mastzellen"--from aniline dyes to DNA chip arrays: a historical review of developments in mast cell research. Methods in molecular biology (Clifton, N.J.) 18 16110145
1994 [Empirical antimicrobial therapy in neutropenic patients. Results of a multicenter study by the Infections in Hematology Study Group of the Paul Ehrlich Society]. Medizinische Klinik (Munich, Germany : 1983) 18 8196571
2021 Mycobacterium tuberculosis PPE10 (Rv0442c) alters host cell apoptosis and cytokine profile via linear ubiquitin chain assembly complex HOIP-NF-κB signaling axis. International immunopharmacology 17 33667868
2016 Survival of mature T cells depends on signaling through HOIP. Scientific reports 16 27786304
2024 RNF31 alleviates liver steatosis by promoting p53/BNIP3-related mitophagy in hepatocytes. Free radical biology & medicine 15 38615890
2024 STING induces HOIP-mediated synthesis of M1 ubiquitin chains to stimulate NF-κB signaling. The EMBO journal 15 39578541
2016 Regulation of Linear Ubiquitin Chain Assembly Complex by Caspase-Mediated Cleavage of RNF31. Molecular and cellular biology 15 27669734
2010 The isolated pancreatic islet as a micro-organ and its transplantation to cure diabetes: celebrating the legacy of Paul Lacy. Islets 15 21099316
2000 Pythium contiguanum nomen novum (syn. Pythium dreschleri Paul), its antagonism to Botrytis cinerea, ITS1 region of its nuclear ribosomal DNA, and its comparison with related species. FEMS microbiology letters 15 10650210
2022 RBCK1 promotes hepatocellular carcinoma metastasis and growth by stabilizing RNF31. Cell death discovery 14 35869046
2017 MicroRNA-378 regulates cell proliferation and migration by repressing RNF31 in pituitary adenoma. Oncology letters 14 29399147
2014 Photobacterium sanctipauli sp. nov. isolated from bleached Madracis decactis (Scleractinia) in the St Peter & St Paul Archipelago, Mid-Atlantic Ridge, Brazil. PeerJ 14 25024905
2004 A putative ariadne-like E3 ubiquitin ligase (PAUL) that interacts with the muscle-specific kinase (MuSK). Gene expression patterns : GEP 13 14678832
1972 Effects of auxin on polyphenol accumulation and the development of phenylalanine ammonia-lyase activity in darkgrown suspension cultures of Paul's Scarlet rose. Planta 13 24481657
2023 The E3 ubiquitin ligase RNF31 mediates the development of ulcerative colitis by regulating NLRP3 inflammasome activation. International immunopharmacology 12 37951199
2016 What Happened to Paul? Manifestation of Abnormal Pain Response for Individuals With Autism Spectrum Disorder. Qualitative health research 12 27117957
2008 Paul Ehrlich: the Nobel Prize in physiology or medicine 1908. International reviews of immunology 12 18300053
2008 RNA-binding protein hoip accelerates polyQ-induced neurodegeneration in Drosophila. Bioscience, biotechnology, and biochemistry 12 18776683
2000 Secular trends in dietary macronutrient intake in Minneapolis-St, Paul, Minnesota, 1980-1992. American journal of epidemiology 12 11085399
2022 Recent advances in "sickle and niche" research - Tribute to Dr. Paul S Frenette. Stem cell reports 11 35830837
2021 RNF31 mediated ubiquitination of A20 aggravates inflammation and hepatocyte apoptosis through the TLR4/MyD88/NF-κB signaling pathway. Chemico-biological interactions 11 34416243
2019 Antibacterial Salinaphthoquinones from a Strain of the Bacterium Salinispora arenicola Recovered from the Marine Sediments of St. Peter and St. Paul Archipelago, Brazil. Journal of natural products 11 31313922
2019 Combination of Proton Therapy and Radionuclide Therapy in Mice: Preclinical Pilot Study at the Paul Scherrer Institute. Pharmaceutics 11 31480730
2019 Auxiliary-assisted chemical ubiquitylation of NEMO and linear extension by HOIP. Communications chemistry 11 31942456
2015 Paul Ehrlich's mastzellen: a historical perspective of relevant developments in mast cell biology. Methods in molecular biology (Clifton, N.J.) 11 25388241
2015 Posttranslational Modification of HOIP Blocks Toll-Like Receptor 4-Mediated Linear-Ubiquitin-Chain Formation. mBio 11 26578682
2014 Vibrio madracius sp. nov. isolated from Madracis decactis (Scleractinia) in St Peter & St Paul Archipelago, Mid-Atlantic Ridge, Brazil. Current microbiology 11 24824949
2008 Historical review. The light and shadow of Paul Kaznelson: his life and contribution to hematology. Annals of hematology 11 18648810
2003 Paul-Bunnell antigen and a possible mechanism of formation of heterophile antibodies in patients with infectious mononucleosis. Acta biochimica Polonica 11 14740007
2022 Mycobiome Diversity of the Cave Church of Sts. Peter and Paul in Serbia-Risk Assessment Implication for the Conservation of Rare Cavern Habitat Housing a Peculiar Fresco Painting. Journal of fungi (Basel, Switzerland) 10 36547596
2013 Ecological, morphological, and molecular studies of Acanthocheilonema odendhali (Nematoda: Filarioidea) in northern fur seals (Callorhinus ursinus) on St. Paul Island, Alaska. Parasitology research 10 23760875
2009 Marinitoga litoralis sp. nov., a thermophilic, heterotrophic bacterium isolated from a coastal thermal spring on Ile Saint-Paul, Southern Indian Ocean. International journal of systematic and evolutionary microbiology 10 19749030
2008 A molecular dynamics simulation study on trapping ions in a nanoscale Paul trap. Nanotechnology 10 21825720
1983 Infectious mononucleosis fifty years after the discovery of the Paul-Bunnell test. Infection 10 6302006
1976 Ammonium Influence on the Growth and Nitrate Reductase Activity of Paul's Scarlet Rose Suspension Cultures. Plant physiology 10 16659637
2022 Genetic deletion and pharmacologic inhibition of E3 ubiquitin ligase HOIP impairs the propagation of myeloid leukemia. Leukemia 9 36352193
2015 Extraintestinal Pathogenic and Antimicrobial-Resistant Escherichia coli Contamination of 56 Public Restrooms in the Greater Minneapolis-St. Paul Metropolitan Area. Applied and environmental microbiology 9 25911488
1986 Paul-Bunnell antigen in murine T cell differentiation: abnormal expression in MRL/Mp-lpr/lpr mice. Journal of immunology (Baltimore, Md. : 1950) 9 3079803
1979 Reactivity of Paul-Bunnell type heterophile antibody in sera from infectious mononucleosis patients with the surface of lymphoid cells carrying Epstein-Barr virus genomes. Microbiology and immunology 9 231730
2025 RNF31 induces paclitaxel resistance by sustaining ALYREF cytoplasmic-nuclear shuttling in human triple-negative breast cancer. Clinical and translational medicine 8 39915011
2021 MyD88-Dependent Signaling Is Required for HOIP Deficiency-Induced Autoinflammation. Journal of immunology (Baltimore, Md. : 1950) 8 34253576
2021 The E3 Ubiquitin Ligase HOIP inhibits Cancer Cell Apoptosis via modulating PTEN stability. Journal of Cancer 8 34659546
2014 Germline polymorphisms in RNF31 regulate linear ubiquitination and oncogenic signaling. Cancer discovery 8 24706658

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