Affinage

RNF31

E3 ubiquitin-protein ligase RNF31 · UniProt Q96EP0

Length
1072 aa
Mass
119.7 kDa
Annotated
2026-04-28
100 papers in source corpus 33 papers cited in narrative 33 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RNF31 (HOIP) is the catalytic E3 ubiquitin ligase subunit of the linear ubiquitin chain assembly complex (LUBAC) that synthesizes Met1-linked (linear) polyubiquitin chains to activate NF-κB signaling and suppress cell death across multiple immune and developmental contexts. HOIP employs a RING/HECT-hybrid two-step mechanism in which RING1-IBR transfers ubiquitin from an E2 onto a thioester intermediate at the RING2 active-site cysteine, and a unique C-terminal Linear ubiquitin chain Determining Domain (LDD) orients the acceptor ubiquitin α-amino group for linear chain formation, as defined by crystal structures of the catalytic core, the ubiquitin-bound state, and the E2~ubiquitin transfer complex (PMID:22863777, PMID:24141947, PMID:26789245). HOIP-dependent linear ubiquitination of NEMO and FADD at TNFR1, TNFR2, CD40, TLR, and STING receptor complexes is essential for canonical NF-κB and JNK activation, and HOIP deficiency causes TNFR1-dependent endothelial lethality, skin inflammation, T cell loss, and sensitization of tumor cells to TNF/IFNγ-mediated and immune cell–mediated killing (PMID:25284787, PMID:21829693, PMID:29728512, PMID:27786304, PMID:35379808, PMID:35688159). Beyond linear chain assembly, HOIP ubiquitinates additional substrates—including ERα, p53, GPx4, YAP, A20, and NLRP3—to regulate their stability, and its own activity is modulated by caspase cleavage during apoptosis, Lys1056 ubiquitination, and interactions with the deubiquitinases OTULIN and CYLD–SPATA2, which counterbalance linear ubiquitin signaling (PMID:24726327, PMID:27545878, PMID:27669734, PMID:26578682, PMID:36279464, PMID:24441041).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2004 Low

    Initial identification of RNF31 as an RBR-family E3 ligase associated with MuSK at neuromuscular junctions provided the first evidence that the gene encodes a ubiquitin ligase, though no catalytic mechanism or signaling function was established.

    Evidence Yeast two-hybrid/pull-down with MuSK cytoplasmic domain and immunolocalization at NMJs

    PMID:14678832

    Open questions at the time
    • Single interaction assay without reciprocal validation
    • No substrate or chain-type specificity determined
    • Functional role at NMJ undefined
  2. 2009 Medium

    Discovery that RNF31 forms a corepressor complex with DAX-1 at steroidogenic gene promoters and stabilizes DAX-1 via monoubiquitination established its first characterized substrate relationship and linked it to transcriptional regulation.

    Evidence ChIP at StAR/CYP19 promoters, Co-IP, siRNA knockdown, gene expression analysis in steroidogenic cells

    PMID:19237537

    Open questions at the time
    • Whether this represents LUBAC-dependent linear ubiquitination or an independent activity was unknown
    • Chain type of monoubiquitination not defined as M1-linked
  3. 2010 Medium

    Identification of HOIP at the CD40 signaling complex and demonstration that its ligase activity is required for CD40-mediated NF-κB activation established HOIP as an activating component of immune receptor signaling.

    Evidence Mass spectrometry of CD40 complexes, dominant-negative catalytic mutant, NF-κB reporter assay

    PMID:20614026

    Open questions at the time
    • Chain type synthesized at CD40 complex not yet characterized
    • Whether HOIP acts as part of LUBAC in this context was unclear
  4. 2011 High

    HOIP-deficient B cells confirmed the essential, non-redundant role of HOIP in CD40 signaling by showing complete loss of NF-κB and JNK activation, IKK recruitment failure, and defective B cell functional responses, all rescued by re-expression.

    Evidence Somatic gene targeting of HOIP in B cell lines, rescue by re-expression, multiple signaling readouts

    PMID:21829693

    Open questions at the time
    • Whether HOIP is required for other TNFR superfamily members beyond CD40 was untested
    • In vivo B cell immune response not examined
  5. 2012 High

    Biochemical dissection revealed HOIP's unique catalytic mechanism—a RING/HECT-hybrid two-step reaction using a thioester intermediate at RING2 and a C-terminal LDD domain that specifies linear (Met1) chain linkage—resolving how LUBAC achieves chain-type specificity.

    Evidence In vitro ubiquitination assays with active-site and domain mutants, cellular NF-κB reporters

    PMID:22863777

    Open questions at the time
    • Structural basis for acceptor ubiquitin orientation not yet visualized
    • How LUBAC accessory subunits regulate HOIP catalysis unknown
  6. 2013 High

    Crystal structures of the HOIP catalytic core with and without ubiquitin revealed the structural basis for linear chain specificity: a zinc-finger and novel C-terminal fold create an acceptor ubiquitin-binding platform positioning the α-amino group for nucleophilic attack.

    Evidence X-ray crystallography (apo and ubiquitin-bound), functional mutagenesis in cells

    PMID:24141947

    Open questions at the time
    • Structure of full-length HOIP in activated state with E2~Ub not yet solved
    • Donor ubiquitin engagement undefined structurally
  7. 2014 High

    Multiple advances defined HOIP's regulatory network and in vivo essentiality: structural characterization of the HOIP PUB–OTULIN interaction revealed phospho-regulated deubiquitinase recruitment; HOIP deficiency caused TNFR1-dependent embryonic-lethal vascular defects; and HOIP was linked to ERα stabilization and cisplatin sensitivity, broadening its substrate repertoire and physiological roles.

    Evidence Crystal/NMR structures of PUB–OTULIN; conditional Hoip KO mice with TNFR1 epistasis; Co-IP/ubiquitination assays for ERα; siRNA screen for cisplatin sensitivity

    PMID:24441041 PMID:24686174 PMID:24726327 PMID:25284787

    Open questions at the time
    • How OTULIN and CYLD coordinate linear chain editing at receptor complexes unknown
    • ERα ubiquitination chain type not determined as linear
    • In vivo relevance of ERα stabilization unconfirmed
  8. 2016 High

    The crystal structure of fully active HOIP RBR bound to E2~ubiquitin revealed the complete catalytic transfer mechanism—an elongated conformation distinct from auto-inhibited RBRs with three ubiquitin-binding sites engaging donor, regulatory, and acceptor ubiquitins—while functional studies showed HOIP is required for T cell survival, is cleaved by caspases during apoptosis to limit linear ubiquitination, and is regulated by Lys1056 ubiquitination in a stimulus-specific manner.

    Evidence X-ray crystallography of HOIP/E2~Ub complex; T cell-specific catalytic-dead knock-in mice; caspase cleavage mapping with mutagenesis; K1056R mutagenesis with TLR4/CD40 signaling assays

    PMID:26578682 PMID:26789245 PMID:27545878 PMID:27669734 PMID:27786304

    Open questions at the time
    • How auto-inhibition is relieved by HOIL-1L/SHARPIN in the full LUBAC complex not structurally resolved
    • Relative contributions of OTULIN vs CYLD–SPATA2 in different signaling contexts unclear
    • Whether caspase cleavage is a feedforward amplification loop in apoptosis not fully tested
  9. 2018 High

    Extension of HOIP's receptor signaling roles to TNFR2 (requiring cIAP1 for recruitment) and skin-specific knockout showing TNFR1-rescuable lethal dermatitis established HOIP as a pan-TNFR family signaling node whose loss triggers tissue-specific inflammatory cell death.

    Evidence TNFR2 complex IP with M1-Ub antibodies and cIAP antagonist; epidermis-specific Hoip KO with TNFR1 epistasis

    PMID:29378181 PMID:29728512

    Open questions at the time
    • Whether HOIP engages all TNFR superfamily members or only specific subsets unknown
    • Mechanism of cIAP1-dependent HOIP recruitment to TNFR2 not defined
  10. 2019 High

    Fragment-based covalent screening targeting the HOIP active-site cysteine yielded the first cell-permeable HOIP inhibitors, validated by co-crystal structures and cellular NF-κB suppression, opening pharmacological targeting of linear ubiquitination.

    Evidence Fragment screen, protein LC-MS, co-crystal structures, chemoproteomics, cell-based NF-κB assays

    PMID:30657686

    Open questions at the time
    • Inhibitor selectivity over other RBR ligases not comprehensively profiled
    • In vivo efficacy not demonstrated
    • No therapeutic window established
  11. 2019 Medium

    Chemically synthesized monoubiquitylated NEMO demonstrated that HOIP RBR alone can extend a pre-primed substrate, establishing a two-step model for NEMO linear ubiquitination where priming and extension have distinct LUBAC subunit requirements.

    Evidence Chemical ubiquitylation via ligation auxiliary, in vitro extension assay with recombinant HOIP RBR

    PMID:31942456

    Open questions at the time
    • Identity of the priming E3 or priming mechanism in cells not established
    • Whether the two-step model applies to substrates beyond NEMO unknown
  12. 2021 Medium

    Studies in dendritic cell-specific HOIP knockouts, plus identification of new substrates (A20, p53, PTEN), revealed cell-type-specific HOIP functions: DC autoinflammation is driven by MyD88/TLR rather than TNFR1, while HOIP-mediated degradation of A20, p53, and PTEN connects linear ubiquitination to inflammation, cell cycle, and PI3K-AKT signaling.

    Evidence DC-specific KO with MyD88/TNFR1 epistasis; Co-IP and ubiquitination/degradation assays for A20, p53, PTEN; mouse colitis and liver injury models

    PMID:33824292 PMID:34253576 PMID:34416243 PMID:34659546

    Open questions at the time
    • Whether A20 and p53 ubiquitination is linear or K48/K63-linked needs clarification
    • PTEN interaction awaits independent validation
    • How HOIP selects among diverse substrates is mechanistically unclear
  13. 2022 High

    Multiple genome-wide CRISPR screens converged on RNF31 as a critical tumor immune-evasion gene: HOIP loss sensitizes cancer cells to TNF-mediated caspase-8-dependent apoptosis and immune cell killing, while new substrates GPx4 (ferroptosis protection), YAP (Hippo pathway), and NLRP3 (inflammasome) expanded HOIP's substrate repertoire.

    Evidence In vivo and in vitro CRISPR screens in pancreatic and colon cancer; pharmacological HOIP inhibition in organoids; Co-IP/ubiquitination for GPx4, YAP, NLRP3; ferroptosis and inflammasome assays

    PMID:34467615 PMID:35379808 PMID:35688159 PMID:36279464 PMID:36581998 PMID:37951199

    Open questions at the time
    • Whether GPx4, YAP, NLRP3 ubiquitination is linear or non-linear chain type needs definitive characterization
    • Therapeutic index of HOIP inhibition for cancer immunotherapy not established
    • Structural basis for substrate selection among diverse targets unknown
  14. 2024 Medium

    HOIP was placed in the STING innate immune pathway: upon STING activation, LUBAC is recruited to LC3B-associated Golgi membranes where HOIP synthesizes M1-linked chains required for downstream NF-κB and IRF3 signaling, establishing a new receptor-proximal context for linear ubiquitination.

    Evidence HOIP KO in THP1 and BMDMs, M1-Ub IP, STING agonist stimulation, Golgi fractionation

    PMID:39578541

    Open questions at the time
    • How LUBAC is recruited to STING-containing Golgi membranes mechanistically undefined
    • Whether LC3B association is required for LUBAC activity at this site not tested
    • Whether STING-dependent LUBAC recruitment occurs in non-myeloid cells unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: how HOIP discriminates among its growing list of substrates for linear versus non-linear ubiquitination, the structural basis of full-length LUBAC auto-inhibition and activation by HOIL-1L and SHARPIN, and whether pharmacological HOIP inhibition can achieve a therapeutic window in vivo for cancer immunotherapy or inflammatory disease.
  • No structure of full-length trimeric LUBAC in auto-inhibited or active state
  • Chain-type specificity for many reported substrates (ERα, p53, PTEN, YAP) not rigorously determined
  • In vivo pharmacology of HOIP inhibitors not reported

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 13 GO:0016874 ligase activity 3
Localization
GO:0005886 plasma membrane 3 GO:0005794 Golgi apparatus 1 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 10 R-HSA-5357801 Programmed Cell Death 7 R-HSA-168256 Immune System 5 R-HSA-392499 Metabolism of proteins 4
Partners
A20CYLDNEMONLRP3OTULINRBCK1SHARPINSPATA2
Complex memberships
LUBAC

Evidence

Reading pass · 33 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 uses a two-step RING/HECT-hybrid mechanism: RING1-IBR catalyzes transfer of ubiquitin from E2 onto a covalent HECT-like thioester intermediate at RING2, then a unique C-terminal Linear ubiquitin chain Determining Domain (LDD) coordinates the acceptor ubiquitin N-terminus for Met1-linked (linear) chain formation. In vitro ubiquitination assays, active-site mutagenesis, biochemical dissection of RING1-IBR and RING2-LDD sub-domains, cellular NF-κB reporter assays The EMBO journal High 22863777
2013 Crystal structures of the HOIP catalytic core in apo form and in complex with ubiquitin revealed a novel C-terminal fold and zinc-finger that form a ubiquitin-binding platform orienting the acceptor ubiquitin α-amino group for nucleophilic attack on the E3~ubiquitin thioester, explaining linear chain specificity. X-ray crystallography (apo and ubiquitin-bound structures), mutagenesis, cellular NF-κB assays Nature High 24141947
2016 Crystal structure of fully active HOIP RBR in complex with an E2~ubiquitin conjugate showed that active HOIP adopts a conformation markedly different from auto-inhibited RBRs, binds E2~ubiquitin in an elongated fashion aligning catalytic centres for HECT-like transfer, and revealed three helix-IBR-fold ubiquitin-binding regions that engage the activated (donor) ubiquitin and an additional regulatory ubiquitin. X-ray crystallography of HOIP RBR/E2~ubiquitin transfer complex, structural comparison with Parkin and HHARI Nature High 26789245
2014 HOIP (RNF31) PUB domain binds the PUB-interacting motif (PIM) of the linear deubiquitinase OTULIN; structural studies defined critical contacts (OTULIN Tyr56); phosphorylation of OTULIN Tyr56 negatively regulates this interaction. HOIP binding to OTULIN recruits OTULIN to the TNF receptor complex to counteract HOIP-dependent NF-κB activation. Co-IP, structural studies (crystal/NMR), phosphorylation site mutagenesis, TNF receptor complex recruitment 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; SPATA2 is required for CYLD recruitment to TNFR1- and NOD2-signaling complexes, and its loss diminishes TNF-induced necroptosis similarly to CYLD loss. Co-IP, signaling complex (TNFR1/NOD2) pull-down, SPATA2 knockout/knockdown with necroptosis readout Cell reports High 27545878
2014 HOIP (RNF31) deficiency causes aberrant TNFR1-mediated endothelial cell death via aberrant complex-II formation, leading to vascularization defects and embryonic lethality; TNFR1 ablation rescues this phenotype, and HOIP catalytic activity is required to prevent TNF-induced cell death. Conditional (Tie2-Cre) and constitutive Hoip knockout mice, genetic epistasis with TNFR1 knockout, cell death assays, complex-II immunoprecipitation Cell reports High 25284787
2014 RNF31 (HOIP) associates with estrogen receptor α (ERα) primarily in the cytosol, increases ERα stability and mono-ubiquitination in a ubiquitin-ligase-activity-dependent manner, and is required for ERα-stimulated proliferation and downstream target gene expression in breast cancer cells. Co-immunoprecipitation, siRNA knockdown, cycloheximide chase, cell-cycle analysis, ubiquitination assays with catalytic mutant Oncogene Medium 24441041
2009 RNF31 forms an in vivo corepressor complex with DAX-1 at the promoters of steroidogenic genes (StAR, CYP19), stabilizes DAX-1 via monoubiquitination, and is required for DAX-1-mediated repression of SF-1-dependent steroidogenic gene transcription. ChIP, Co-IP, siRNA knockdown, gene expression analysis, co-expression studies in steroidogenic tissues Molecular and cellular biology Medium 19237537
2010 HOIP (RNF31/PAUL/ZIBRA) is recruited to the CD40 signaling complex in a TRAF2-dependent manner; its ubiquitin ligase activity is required for CD40-mediated NF-κB activation, and a catalytic-dead HOIP mutant acts as a dominant negative. Mass spectrometry of CD40 signaling complexes, Co-IP, dominant-negative ligase-dead mutant, NF-κB reporter assay PloS one Medium 20614026
2011 HOIP is essential for CD40 signaling: HOIP-deficient B cells fail to activate NF-κB and JNK via CD40, exhibit impaired IKK recruitment to the CD40 signaling complex, and show defective CD80 upregulation and germline IgE transcription; HOIP re-expression restores all defects. Somatic gene targeting to generate HOIP-deficient B cell lines, signaling assays (NF-κB, JNK, IKK recruitment), rescue by re-expression PloS one High 21829693
2016 HOIP cleavage by caspases 3 and 6 at Asp348, Asp387, and Asp390 during apoptosis reduces linear ubiquitination of NEMO and FADD; the N-terminal cleavage fragment retains binding to OTULIN and CYLD-SPATA2 while the C-terminal fragment retains NF-κB activity; cleavage-site mutation inhibits TNF-α-induced apoptosis. Caspase cleavage assays, site-directed mutagenesis of cleavage sites, linear ubiquitination assays, Co-IP with deubiquitinases, apoptosis assays Molecular and cellular biology High 27669734
2017 FADD is identified as a substrate for LUBAC linear ubiquitination in addition to NEMO; HOIP is cleaved predominantly by caspase at Asp390 during apoptosis and is subsequently subject to proteasomal degradation, decreasing linear ubiquitination of both NEMO and FADD. Linear ubiquitination assays, caspase cleavage assays, proteasome inhibitor experiments, Co-IP Biochemical and biophysical research communications Medium 28189684
2015 Ubiquitination of HOIP at Lys1056 (C-terminal lysine) induces a conformational change that suppresses HOIP catalytic activity and terminates TLR4/LPS-induced NF-κB signaling, but does not affect CD40-induced NF-κB activation, identifying a stimulus-specific regulatory PTM. Site-directed mutagenesis (K1056R), in vitro ubiquitination assays, NF-κB reporter assays with TLR4 and CD40 stimulation mBio Medium 26578682
2018 HOIP (and cIAP1) are recruited to the TNFR2 signaling complex; HOIP mediates M1-linked polyubiquitination at this complex; cIAP1 antagonism prevents HOIP recruitment; both HOIP and cIAP1 are required for TNFR2-induced canonical NF-κB activation. Signaling complex immunoprecipitation, M1/K63 linkage-specific ubiquitin antibodies, cIAP antagonist treatment, NF-κB activation assays Biochemical pharmacology Medium 29378181
2014 HOIP-depleted cells are hypersensitive to cisplatin-induced apoptosis through enhanced caspase-8/caspase-3-dependent apoptosis that requires ATM (but not ATR) checkpoint activation; basal and cisplatin-induced JNK activity is enhanced in HOIP-depleted cells, and JNK inhibition reverses apoptotic hyperactivation. siRNA screen, siRNA knockdown, caspase activation assays, ATM/ATR inhibitors, JNK inhibitor rescue, apoptosis assays Cancer research Medium 24686174
2022 LUBAC (HOIP) binds and stabilizes GPx4 via linear ubiquitination both basally and under oxidative stress; LUBAC deficiency sensitizes cells to ferroptosis by promoting GPx4 degradation and downstream lipid peroxidation, identifying GPx4 as a key LUBAC substrate. Co-IP, linear ubiquitination assays, ferroptosis assays (lipid peroxidation), LUBAC-deficient cells, GPx4 stability (cycloheximide chase) Proceedings of the National Academy of Sciences of the United States of America Medium 36279464
2022 RNF31 (HOIP) protects tumor cells from TNF-mediated caspase-8 cleavage and apoptosis; CRISPR knockout of Rnf31 sensitizes pancreatic cancer cells to CD8+ T cell killing in a TNF-dependent manner, increases intratumoral CD8+ T cell infiltration and effector function in vivo, and reduces tumor growth. CRISPR-Cas9 in vitro and in vivo screens, genetic knockout, caspase-8 cleavage assays, orthotopic transplantation into immune-competent mice Nature communications High 35379808
2022 Genetic and pharmacological ablation of RNF31 sensitizes cancer cells to NK and CD8+ T cell killing in a TNF-dependent manner by 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. Genome-wide CRISPR-Cas9 screens under NK and CD8+ T cell pressure, genetic knockout, pharmacologic inhibition, TNF receptor complex immunoprecipitation, organoid killing assays Cell reports. Medicine High 35688159
2021 HOIP-deficient tumor cells show increased sensitivity to combined TNF and IFN-γ, engaging both intrinsic and extrinsic apoptotic machinery through a transcription-dependent cell death pathway; both genetic deletion and pharmacological inhibition of HOIP augment this sensitivity. CRISPR/Cas9 screening, genetic deletion, pharmacological inhibition, NK/CD8+ T cell killing assays, cytokine (TNF+IFN-γ) treatment, apoptosis pathway dissection EMBO reports Medium 34467615
2018 Epidermis-specific knockout of RNF31 in mice causes postnatal lethality due to severe skin inflammation triggered by TNF-α-induced apoptosis in keratinocytes; RNF31 deficiency impairs TNF-α-induced NF-κB activation and increases apoptosis; deletion of TNFR1 rescues lethality and skin inflammation. Tissue-specific conditional knockout, genetic epistasis with TNFR1 knockout, NF-κB activation assays, apoptosis assays in primary keratinocytes Journal of immunology High 29728512
2016 HOIP ubiquitin ligase activity is required for mature T cell survival; T-HOIPΔlinear mice show reduced CD4+/CD8+ T cell numbers and defective NKT development; HOIP-deficient CD4+ T cells fail to phosphorylate IκBα and JNK upon TCR stimulation; reduced CD127 expression causes mature T cell apoptosis, and enforced CD127 expression rescues CD8+ T cell development. Conditional knockout (ubiquitin ligase-dead knock-in), flow cytometry, signaling assays, apoptosis assays, CD127 rescue experiment Scientific reports Medium 27786304
2024 STING activation recruits LUBAC (HOIP) to LC3B-associated Golgi membranes where it synthesizes M1-linked ubiquitin chains; loss of HOIP prevents M1-Ub chain formation and reduces both NF-κB and IRF3 signaling downstream of STING without affecting STING activation itself. HOIP knockout in THP1 monocytes and mouse BMDMs, M1-ubiquitin chain immunoprecipitation, STING activation assays, fractionation/localization to Golgi membranes The EMBO journal Medium 39578541
2021 RNF31 interacts with A20 via its RBR structural domain, promotes K63-linked ubiquitination of A20 leading to A20 proteasomal degradation, thereby activating the TLR4/MyD88/NF-κB pathway and aggravating hepatocyte apoptosis and inflammation in acute liver injury. Co-IP, actinomycin tracing, proteasome inhibitor experiments, ubiquitination assays, siRNA knockdown, mouse model of acute liver injury Chemico-biological interactions Medium 34416243
2019 Fragment-based covalent ligand screening targeting the active-site cysteine of HOIP identified electrophilic fragments that inhibit HOIP catalytic activity; crystal structures of HOIP-inhibitor complexes enabled structure-based development; cell-permeable compounds inhibit HOIP and NF-κB activation in mammalian cells as shown by chemoproteomics. Fragment-based covalent screening, protein LC-MS, in vitro ubiquitination assays, protein crystallography, cell-based NF-κB assays, chemoproteomics Journal of the American Chemical Society High 30657686
2022 RNF31 associates with YAP protein, facilitates YAP poly-ubiquitination and proteasomal degradation at K76, and thereby suppresses Hippo/YAP/PD-L1 signaling in triple-negative breast cancer cells. Co-IP, ubiquitination assays, site-specific mutagenesis (YAP K76), immunoblots, gene expression profiling, xenograft models Journal of experimental & clinical cancer research Medium 36581998
2021 RNF31 interacts with p53 via its PUB domain, promotes p53 ubiquitination and proteasomal degradation; RNF31 depletion alleviates p53 degradation (inhibited by MG132), and this RNF31/p53 axis drives colorectal cancer cell proliferation. Co-IP with truncated RNF31 domain constructs, cycloheximide chase, proteasome inhibitor (MG132), ubiquitination assays, siRNA knockdown Cell death discovery Medium 33824292
2024 RNF31 promotes p53 ubiquitination and proteasomal degradation in hepatocytes; reduced p53 levels increase BNIP3 expression, promoting mitophagy and reducing hepatic steatosis; RNF31-containing small extracellular vesicles from mesenchymal stem cells reduce steatosis in HFD-fed mice. Ubiquitination assays, co-IP, siRNA knockdown, mt-Keima mitophagy imaging, RNA-seq, in vivo HFD mouse model with sEV delivery Free radical biology & medicine Medium 38615890
2022 RBCK1 (HOIL-1L) interacts with RNF31 (HOIP) and represses its ubiquitination and proteasomal degradation, thereby stabilizing RNF31 protein levels in hepatocellular carcinoma cells. Co-IP, ubiquitination assays, proteasome inhibitor experiments, siRNA/overexpression in HCC cells Cell death discovery Medium 35869046
2023 RNF31 interacts with NLRP3 through its RBR structural domain, promotes K63-linked ubiquitination of NLRP3 leading to NLRP3 stabilization, and thereby activates the NLRP3 inflammasome during ulcerative colitis. Co-IP with domain-mapping, K63-linkage specific ubiquitination assays, RNF31 knockdown in cells and mouse DSS-colitis model International immunopharmacology Medium 37951199
2004 RNF31 (PAUL/ZIBRA) was identified as an Ariadne-like RBR ubiquitin ligase that binds to the cytoplasmic domain of the muscle-specific receptor tyrosine kinase MuSK and is present at neuromuscular junctions. Yeast two-hybrid or pull-down (interaction with MuSK cytoplasmic domain), expression profiling in developing mouse tissues, immunolocalization at NMJs Gene expression patterns Low 14678832
2019 Chemically synthesized monoubiquitylated NEMO (NEMOCoZi-Ub) is accepted as a substrate for linear extension by the HOIP RBR domain alone, demonstrating that NEMO linear ubiquitylation occurs in two steps: an initial priming event and a separate extension step requiring different LUBAC components. Chemical ubiquitylation using ligation auxiliary, in vitro linear extension assay with recombinant HOIP RBR, biophysical affinity measurements Communications chemistry Medium 31942456
2021 In dendritic cell-specific HOIP knockout mice, autoinflammation is not rescued by TNFR1 deletion but is rescued by antibiotic treatment or MyD88 deficiency, placing HOIP upstream of MyD88-dependent TLR signaling in preventing DC-mediated autoinflammation. LPS-stimulated HOIP-deficient DCs show enhanced cell death and elevated IL-1α/IL-1β. DC-specific conditional KO, genetic epistasis with TNFR1-KO and MyD88-KO, antibiotic treatment, LPS stimulation, cytokine assays Journal of immunology Medium 34253576
2021 HOIP inhibits cancer cell apoptosis by associating with PTEN and promoting PTEN proteasomal degradation; HOIP depletion causes cell cycle arrest and apoptosis that can be rescued by PTEN silencing, placing HOIP upstream of PTEN in the PI3K-AKT survival pathway. Co-IP, PTEN stability assay (cycloheximide chase + MG132), siRNA double knockdown (HOIP+PTEN), apoptosis/cell-cycle assays Journal of Cancer Medium 34659546

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 217 25284787
2015 Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia. The Journal of experimental medicine 216 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 191 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
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
2016 Structure of a HOIP/E2~ubiquitin complex reveals RBR E3 ligase mechanism and regulation. Nature 148 26789245
2009 Our perception of the mast cell from Paul Ehrlich to now. European journal of immunology 138 19130582
2020 Mast cells as a unique hematopoietic lineage and cell system: From Paul Ehrlich's visions to precision medicine concepts. Theranostics 136 32929378
2016 SPATA2-Mediated Binding of CYLD to HOIP Enables CYLD Recruitment to Signaling Complexes. Cell reports 114 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 96 30657686
2014 The atypical ubiquitin ligase RNF31 stabilizes estrogen receptor α and modulates estrogen-stimulated breast cancer cell proliferation. Oncogene 81 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 43 36279464
2022 RNF31 inhibition sensitizes tumors to bystander killing by innate and adaptive immune cells. Cell reports. Medicine 41 35688159
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
2022 Loss of Rnf31 and Vps4b sensitizes pancreatic cancer to T cell-mediated killing. Nature communications 39 35379808
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
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
2016 Paul Ehrlich and the Early History of Granulocytes. Microbiology spectrum 35 27726791
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
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
2021 HOIP limits anti-tumor immunity by protecting against combined TNF and IFN-gamma-induced apoptosis. EMBO reports 28 34467615
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
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
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 25 9138526
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
2013 pAUL: a gateway-based vector system for adaptive expression and flexible tagging of proteins in Arabidopsis. PloS one 21 23326506
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
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
2022 From magic bullets to modern therapeutics: Paul Ehrlich, the German immunobiologist and physician coined the term 'complement'. Molecular immunology 19 36027818
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
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 18 32308514
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
2024 RNF31 alleviates liver steatosis by promoting p53/BNIP3-related mitophagy in hepatocytes. Free radical biology & medicine 15 38615890
2016 Survival of mature T cells depends on signaling through HOIP. Scientific reports 15 27786304
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
2016 Regulation of Linear Ubiquitin Chain Assembly Complex by Caspase-Mediated Cleavage of RNF31. Molecular and cellular biology 14 27669734
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
2024 STING induces HOIP-mediated synthesis of M1 ubiquitin chains to stimulate NF-κB signaling. The EMBO journal 13 39578541
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
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
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
2023 The E3 ubiquitin ligase RNF31 mediates the development of ulcerative colitis by regulating NLRP3 inflammasome activation. International immunopharmacology 10 37951199
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
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 10 31313922
2019 Combination of Proton Therapy and Radionuclide Therapy in Mice: Preclinical Pilot Study at the Paul Scherrer Institute. Pharmaceutics 10 31480730
2019 Auxiliary-assisted chemical ubiquitylation of NEMO and linear extension by HOIP. Communications chemistry 10 31942456
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
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