Affinage

RHBDF2

Inactive rhomboid protein 2 · UniProt Q6PJF5

Length
856 aa
Mass
96.7 kDa
Annotated
2026-06-10
93 papers in source corpus 33 papers cited in narrative 32 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

RHBDF2 (iRhom2) is a catalytically inactive rhomboid pseudoprotease that functions as the obligate regulatory cofactor of the metalloprotease ADAM17/TACE, governing where, when, and against which substrates ADAM17 sheds membrane proteins (PMID:22246777, PMID:22246778, PMID:38781971). iRhom2 binds nascent ADAM17 in the ER and is required for its exit, furin-mediated maturation, and trafficking to the cell surface, controlling TNFα shedding in hematopoietic and immune cells in a tissue-selective manner distinct from its paralog iRhom1 (PMID:22246777, PMID:22246778, PMID:23348744). Cryo-EM structures establish the molecular basis of this partnership: the first transmembrane domain of iRhom2 engages the ADAM17 TMD to drive maturation, while a unique iRhom2 extracellular domain retains the cleaved ADAM17 prodomain to prevent premature activation, and loss of the prodomain mobilizes the protease to engage substrates (PMID:28104813, PMID:38781971, PMID:40512800). The interaction is reciprocally stabilizing—iRhom2 stability depends on ADAM17 binding (PMID:32060096). Activation is licensed through the iRhom2 N-terminal cytoplasmic tail: ERK1/2- and RSK2-dependent phosphorylation upon shedding stimuli recruits 14-3-3 proteins to dissociate ADAM17 from iRhom2 and trigger surface cleavage, with an intrinsic RKR motif and the partner FRMD8 acting as repressors (PMID:28432785, PMID:29045841, PMID:40885391). Through ADAM17, iRhom2 governs substrate-selective shedding of TNFα, EGF-family ligands, TNF receptors, CSF1R, MHC class I, and TREM2, coupling it to inflammation, EGFR signaling, and myeloid biology (PMID:23801765, PMID:26535007, PMID:27601030, PMID:40081988, PMID:38570362). Gain-of-function mutations in the iRhom2 N-terminal cytoplasmic domain cause Tylosis with Esophageal Cancer (TOC) by increasing iRhom2 stability and ADAM17-driven EGFR-ligand shedding, producing keratinocyte hyperproliferation and a wound-healing-like phenotype (PMID:22265016, PMID:22638770, PMID:24643277, PMID:24825892). Independent of ADAM17, iRhom2 supports innate antiviral immunity by stabilizing and trafficking STING and VISA/MAVS (PMID:27428826, PMID:29155878), and an SPC-cleaved N-terminal fragment translocates to the nucleus to bind CtBPs and reprogram the keratinocyte transcriptome (PMID:38183983).

Mechanistic history

Synthesis pass · year-by-year structured walk · 25 steps
  1. 2012 High

    Established the founding function of iRhom2 by answering how ADAM17/TACE leaves the ER to become active, defining iRhom2 as an essential trafficking cofactor required for TNFα shedding.

    Evidence Knockout mice, co-immunoprecipitation, subcellular fractionation, and TNF shedding assays, replicated across two simultaneous papers

    PMID:22246777 PMID:22246778

    Open questions at the time
    • Did not define the structural basis of the iRhom2-ADAM17 interaction
    • Mechanism of activation versus trafficking not separated
  2. 2012 Medium

    Showed iRhom2's role in TNFα release is specific and selective downstream of Toll-like receptors, not a general secretory defect.

    Evidence ENU-induced missense mutation in mice with cytokine secretion assays distinguishing TNFα from IL-6 in macrophages

    PMID:22550345

    Open questions at the time
    • Did not map the affected residue to a mechanistic step
    • Single lab
  3. 2012 High

    Connected iRhom2 to human disease, establishing N-terminal cytoplasmic-domain missense mutations as the cause of Tylosis with Esophageal Cancer with dysregulated EGFR signaling.

    Evidence Targeted capture sequencing and patient-derived keratinocyte proliferation/migration assays, replicated in additional families

    PMID:22265016 PMID:22638770

    Open questions at the time
    • Did not establish whether mutations were gain- or loss-of-function at the time
    • Link between EGFR changes and ADAM17 not yet mechanistic
  4. 2013 High

    Resolved tissue specificity by showing iRhom2 controls TACE maturation selectively in immune cells while iRhom1 supports it elsewhere, and that the N-terminal cytoplasmic domain dictates substrate-selective stimulated shedding.

    Evidence Rhbdf2-deficient mouse models, arthritis models, and iRhom2 domain-deletion rescue in MEFs with multiple substrates

    PMID:23348744 PMID:23801765

    Open questions at the time
    • Did not define how the cytoplasmic domain selects substrates
    • Signaling inputs to the domain unknown
  5. 2014 High

    Demonstrated that TOC mutations are gain-of-function, increasing iRhom2 stability and ADAM17-driven EGF-ligand/cytokine shedding to produce keratinocyte hyperproliferation, tumorigenesis, and accelerated wound healing.

    Evidence TOC patient keratinocytes and mouse N-terminal-mutant models with ADAM17 activity, amphiregulin secretion, and in vivo tumor/wound assays

    PMID:24643277 PMID:24825892

    Open questions at the time
    • Reported partly ADAM17-independent amphiregulin effects without a defined alternative mechanism
    • Single lab for each model
  6. 2014 Medium

    Identified upstream transcriptional control, placing iRhom2 as a p63 target gene linking it to keratinocyte stress and survival responses.

    Evidence Reporter assays, ChIP for p63 binding, and iRhom2 knockdown with oxidative stress readouts in keratinocytes

    PMID:29523849

    Open questions at the time
    • Did not connect transcriptional regulation to ADAM17 activity
    • Single lab
  7. 2015 Medium

    Linked iRhom2 to TNF-receptor biology by showing N-terminal deletions increase ADAM17 activity and TNFR shedding, conferring resistance to TNF-induced cell death.

    Evidence Genetic screen with iRhom-ΔN constructs, ADAM17 inhibitors, and TOC patient keratinocytes

    PMID:26535007

    Open questions at the time
    • Did not establish in vivo relevance of TNFR shedding
    • Single lab
  8. 2016 High

    Revealed an ADAM17-independent role in innate antiviral immunity, with iRhom2 controlling STING trafficking and stability against DNA viruses.

    Evidence iRhom2-deficient cells and mice, Co-IP, ubiquitination assays, and HSV-1 challenge defining two distinct mechanisms (TRAPβ recruitment and EIF3S5 deubiquitination)

    PMID:27428826

    Open questions at the time
    • Did not reconcile pseudoprotease iRhom2 acting outside the secretory/ADAM17 axis structurally
    • Direct vs. indirect recruitment of cofactors not fully resolved
  9. 2016 Medium

    Extended the ADAM17-substrate repertoire to CSF1R, linking iRhom2 to myeloid surface-receptor levels and progenitor competitiveness.

    Evidence Mixed bone marrow chimeras, degradomics screen, and flow cytometry in iRhom2-/- mice

    PMID:27601030

    Open questions at the time
    • Did not establish physiological consequences beyond competitive repopulation
    • Single lab
  10. 2017 High

    Defined the activation switch: phosphorylation of the iRhom2 N-terminus and 14-3-3 recruitment dissociate ADAM17 from iRhom2 to license surface shedding.

    Evidence Co-IP, phosphorylation/phosphoproteomics, 14-3-3 binding, and primary macrophage shedding assays, independently replicated across two papers

    PMID:28432785 PMID:29045841

    Open questions at the time
    • Did not identify all kinases and adaptors feeding the switch
    • Structural consequence of dissociation not visualized
  11. 2017 Medium

    Mapped the physical TMD interface, showing iRhom2 TMD1 contacts the ADAM17 TMD and that this contact is required for TNFα shedding.

    Evidence Structural modeling, mutagenesis (sinecure allele), and double-mutant mouse analysis

    PMID:28104813

    Open questions at the time
    • Modeling-based rather than experimental structure
    • Single lab
  12. 2017 Medium

    Identified post-translational positive regulation, with Uev1A-Ubc13 promoting K63-linked ubiquitination of iRhom2 to enhance TACE maturation upon TNFα stimulation.

    Evidence Co-IP, ubiquitination assays, and overexpression-based TACE maturation assays

    PMID:29069608

    Open questions at the time
    • Largely overexpression-based without in vivo confirmation
    • Ubiquitination site not defined
  13. 2017 Medium

    Generalized the antiviral role to RNA viruses, showing iRhom2 stabilizes VISA/MAVS by promoting degradation of the E3 ligases RNF5 and MARCH5.

    Evidence iRhom2-deficient cells, viral infection, ubiquitination, and VISA stability assays

    PMID:29155878

    Open questions at the time
    • Mechanism of selective E3-ligase degradation not fully resolved
    • Single lab
  14. 2020 Medium

    Established reciprocal dependence and refined the activation interface, showing iRhom2 stability requires ADAM17 and that extracellular juxtamembrane domains plus the TMD interaction govern substrate selectivity.

    Evidence Endogenous protein analysis in ADAM17-/- cells and domain-swap/point mutants in Adam17-/- and iRhom1/2-/- cells with shedding assays

    PMID:32060096 PMID:32103528

    Open questions at the time
    • Did not yet provide an experimental structure
    • Substrate-selection code not fully decoded
  15. 2021 Medium

    Identified iRhom2 turnover and metabolic-disease roles, with TRIM31 driving proteasomal degradation of iRhom2 and hepatic iRhom2 binding MAP3K7 to promote NF-κB/JNK and insulin-signaling defects under high-fat diet.

    Evidence Co-IP, proteasomal degradation assays, and hepatocyte-specific/myeloid-specific KO and transgenic mice with bone marrow transplantation

    PMID:32592194 PMID:35217669

    Open questions at the time
    • MAP3K7 binding role versus canonical ADAM17 function not fully separated
    • Single lab per finding
  16. 2022 Medium

    Placed iRhom2 in an oncogenic feedback loop, with mutant KRAS-driven ERK1/2 phosphorylating iRhom2 to recruit 14-3-3 and drive ADAM17-dependent ERBB-ligand shedding in lung cancer.

    Evidence Lung cancer cell lines, iRhom2 KO, phosphorylation/14-3-3 recruitment, and tumor xenografts

    PMID:35971826

    Open questions at the time
    • Did not define which ERK-dependent residues are KRAS-specific
    • Single lab
  17. 2023 Medium

    Defined lipid-based regulation of iRhom2, with ZDHHC3 palmitoylating C476 to promote membrane translocation and block TRIM31-mediated degradation.

    Evidence S-palmitoylation assays, C476 mutagenesis, Co-IP, and ZDHHC3 KO hepatocytes with in vivo models

    PMID:37544908

    Open questions at the time
    • Did not establish how palmitoylation intersects with the activation switch
    • Single lab
  18. 2023 Medium

    Showed a feed-forward loop in epithelia where EGFR signaling transcriptionally upregulates iRhom2 to drive ADAM17-mediated sIL-6R release and IL-6 trans-signaling.

    Evidence iRhom2 knockdown, ADAM17 surface and sIL-6R release assays, and ERK inhibition in mammary epithelial cells

    PMID:37271223

    Open questions at the time
    • Did not define the transcription factor mediating EGFR-driven induction
    • Single lab
  19. 2024 High

    Provided the first experimental structures of the ADAM17/iRhom2 complex, revealing trafficking, prodomain-retention inhibition, and prodomain-loss activation as three distinct regulatory mechanisms.

    Evidence Cryo-EM of inactive and active states with functional validation

    PMID:38781971

    Open questions at the time
    • Did not resolve cytoplasmic activation elements at high resolution
    • Dynamics of prodomain release not directly observed
  20. 2024 High

    Discovered a moonlighting nuclear function, where SPC cleavage liberates an iRhom2 N-terminal fragment that enters the nucleus, binds CtBPs, and reprograms the keratinocyte transcriptome, with elevation in psoriasis and TOC skin.

    Evidence Biochemical cleavage assays, nuclear fractionation, CtBP Co-IP, RNA-seq, and patient skin biopsies

    PMID:38183983

    Open questions at the time
    • Did not define the nuclear fragment's direct DNA/chromatin targets
    • Relationship to membrane-bound iRhom2 pool unclear
  21. 2024 Medium

    Refined cytoplasmic regulation, identifying a phosphorylation-independent 14-3-3 site spanning TOC mutations and distinguishing substrate-selective TOC effects from the binding/stability-destroying cub deletion.

    Evidence 14-3-3 binding and ADAM17 activity assays with TOC and cub allele mutagenesis and patient-cell comparison

    PMID:38409522

    Open questions at the time
    • Did not structurally resolve the non-canonical 14-3-3 site
    • Single lab
  22. 2024 Medium

    Extended iRhom2-ADAM17 control to additional immune substrates, regulating MHC-I shedding/surface expression (CD8+ T-cell activation) and TREM2 shedding (microglial phagocytosis of amyloid β).

    Evidence High-resolution proteomics and functional immune/phagocytosis assays in iRhom2-deficient macrophages and microglia

    PMID:38570362 PMID:40081988

    Open questions at the time
    • Did not establish in vivo consequences in neurodegeneration or anti-tumor immunity
    • Single lab per finding
  23. 2025 High

    Resolved zymogen-bound architecture and inhibitory mechanisms, showing how the prodomain and the MEDI3622 antibody inhibit ADAM17 and identifying an iRhom2 membrane-proximal cytoplasmic reentry loop in activation.

    Evidence Cryo-EM of the ADAM17 zymogen/iRhom2 complex with cellular functional validation

    PMID:40512800

    Open questions at the time
    • Did not capture the fully activated, substrate-engaged state dynamics
    • Cytoplasmic switch elements only partly resolved
  24. 2025 Medium

    Integrated the cytoplasmic regulatory logic, showing RSK2 recruitment and phospho-ERK activate the complex, FRMD8 stabilization inhibits stimulated activity, and an RKR motif represses unstimulated ADAM17.

    Evidence Proteomic, genetic, and biochemical approaches with kinase-recruitment, FRMD8 overexpression, and RKR mutagenesis ADAM17 activity assays

    PMID:40885391

    Open questions at the time
    • Did not define how the three mechanisms are temporally coordinated
    • Single lab
  25. 2025 Medium

    Linked iRhom2-STING signaling to neuroinflammatory disease and identified an m6A-based expression control, with microglial RHBDF2 driving STING-TBK1-IRF3/p65 and YTHDF1 enhancing RHBDF2 mRNA expression.

    Evidence Co-IP, microglia-specific RHBDF2 knockdown in MCAO/R mice, MeRIP, and RNA-seq

    PMID:40898058

    Open questions at the time
    • Did not separate STING-pathway effects from ADAM17-dependent functions
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple cytoplasmic inputs (ERK/RSK2 phosphorylation, 14-3-3, RKR motif, FRMD8, palmitoylation, ubiquitination) are integrated into a single temporally ordered activation switch, and how iRhom2's ADAM17-independent roles (STING/MAVS trafficking, nuclear CtBP signaling) are structurally and mechanistically reconciled with its pseudoprotease architecture, remains unresolved.
  • No unified structural model of the cytoplasmic activation switch
  • Mechanism distributing iRhom2 between membrane, antiviral, and nuclear pools undefined
  • Direct nuclear-fragment chromatin targets unidentified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 6 GO:0060090 molecular adaptor activity 4 GO:0140313 molecular sequestering activity 2
Localization
GO:0005886 plasma membrane 4 GO:0005783 endoplasmic reticulum 2 GO:0005634 nucleus 1 GO:0005739 mitochondrion 1
Pathway
R-HSA-168256 Immune System 6 R-HSA-162582 Signal Transduction 5 R-HSA-1643685 Disease 4 R-HSA-392499 Metabolism of proteins 4 R-HSA-9609507 Protein localization 2
Partners
ADAM17CTBPFRMD8MAP3K7MAVSSTING1TRIM31ZDHHC3
Complex memberships
iRhom2-ADAM17 sheddase complex

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2012 iRhom2 (RHBDF2) binds TACE (ADAM17) and is required for its exit from the endoplasmic reticulum, enabling furin-mediated maturation and trafficking of TACE to the cell surface where TNF cleavage occurs; in the absence of iRhom2, TACE fails to exit the ER and TNF shedding is abrogated. Mouse knockout, co-immunoprecipitation, subcellular fractionation, TNF shedding assays Science High 22246777 22246778
2012 iRhom2 interacts with TACE and is critical for TACE maturation and trafficking to the cell surface specifically in hematopoietic cells, controlling TNFα shedding in innate immune responses to LPS and Listeria infection. Gene-targeted iRhom2-deficient mice, co-immunoprecipitation, TNFα shedding assays, infection models Science High 22246777 22246778
2012 A missense mutation in iRhom2 impairs TLR-induced TNFα secretion in macrophages but does not affect IL-6 secretion, establishing a specific and selective role for iRhom2 in TNFα secretion downstream of Toll-like receptors. ENU-induced missense mutation in mice, cytokine secretion assays in macrophages Blood Medium 22550345
2012 Missense mutations in RHBDF2 (p.Ile186Thr and p.Pro189Leu in the N-terminal cytoplasmic domain) cause Tylosis with Esophageal Cancer (TOC); tylotic keratinocytes show altered RHBDF2 distribution, decreased total EGFR levels, and increased proliferative and migratory potential, indicating dysregulated EGFR signaling. Targeted capture sequencing, immortalized patient keratinocytes, immunohistochemistry, proliferation and migration assays American Journal of Human Genetics High 22265016 22638770
2013 iRHOM2 controls the tissue-specific maturation of TACE; inactivation of Rhbdf2 selectively prevents TACE maturation in immune cells without affecting its function in other tissues, where the related iRHOM1 supports TACE maturation and EGFR ligand shedding. Rhbdf2-deficient mouse models, K/BxN inflammatory arthritis model, TNF shedding assays in mouse and human cells Journal of Clinical Investigation High 23348744
2013 iRhom2 controls the substrate selectivity of stimulated ADAM17-dependent ectodomain shedding; the N-terminal cytoplasmic domain of iRhom2 is required for stimulated shedding of HB-EGF and Kit ligand 2 but not TGFα, and rescues shedding when restored by wild-type iRhom2 but not an N-terminal deletion mutant. iRhom2-/- mouse embryonic fibroblasts, shedding assays, siRNA knockdown, rescue with wild-type vs. deletion constructs PNAS High 23801765
2014 TOC-associated gain-of-function mutations in iRHOM2 increase the maturation and activity of ADAM17 in epidermal keratinocytes, resulting in upregulated shedding of EGF-family growth factors and pro-inflammatory cytokines, increased EGFR activity, altered desmosome processing, and a constitutive wound-healing-like phenotype. TOC patient-derived keratinocytes, ADAM17 activity assays, Western blotting, immunostaining Human Molecular Genetics High 24643277
2014 N-terminal domain mutations in Rhbdf2 increase iRhom2 protein stability and drive EGFR hyperactivation by augmenting secretion of the EGF family ligand amphiregulin, independently of ADAM17 activity; these stable variants cause accelerated wound healing and tumorigenesis in vivo. Mouse models with N-terminal iRhom2 mutations, amphiregulin secretion assays, wound healing assays, in vivo tumor models PNAS Medium 24825892
2015 Deletions in the N-terminal cytoplasmic domain of iRhom2 (or iRhom1) increase ADAM17 activity and TNFR shedding, leading to resistance to TNF-induced cell death; TOC patient keratinocytes exhibit increased TNFR1 shedding compared to healthy donors. Genetic screen, fibrosarcoma cell lines with iRhom-ΔN constructs, ADAM17 inhibitors, TOC patient keratinocytes Science Signaling Medium 26535007
2016 iRhom2 is required for innate immune signaling to DNA viruses by directly associating with STING; iRhom2 recruits TRAPβ to the STING complex to facilitate STING trafficking from the ER to perinuclear microsomes, and separately recruits deubiquitinase EIF3S5 to remove K48-linked polyubiquitin chains from STING, preventing its degradation. iRhom2-deficient cells and mice, co-immunoprecipitation, viral infection assays, ubiquitination assays, HSV-1 challenge Nature Immunology High 27428826
2016 iRhom2 regulates CSF1R cell surface expression by controlling ADAM17-mediated shedding of CSF1R from myeloid cells; in iRhom2-/- mice, membrane-bound CSF1R accumulates on myeloid cells and iRhom2-/- bone marrow progenitors show competitive repopulation advantages under pressure. Mixed bone marrow chimeras, degradomics screen, flow cytometry, in vitro CSF1 response assays European Journal of Immunology Medium 27601030
2017 iRhom2 remains associated with TACE throughout the secretory pathway and is stabilized at the cell surface by this interaction; ERK1/2-mediated phosphorylation of the cytoplasmic N-terminus of iRhom2 and subsequent 14-3-3 protein binding alter its interaction with mature TACE, licensing TACE proteolytic activity at the plasma membrane to trigger inflammatory responses in macrophages. Co-immunoprecipitation, phosphorylation assays, 14-3-3 binding assays, primary macrophage TNF shedding assays, cell surface biotinylation eLife High 28432785
2017 MAP kinase-dependent phosphorylation of the iRhom2 N-terminal cytoplasmic tail triggered by shedding stimuli recruits 14-3-3 proteins, enforcing dissociation of TACE from iRhom2 complexes and promoting cleavage of TACE substrates on the cell surface. Phosphoproteomics, 14-3-3 binding assays, co-immunoprecipitation, shedding assays Cell Reports High 29045841
2017 Structural modeling identified transmembrane domain residues in ADAM17 that are crucial for Rhbdf2-ADAM17-dependent proteolysis; the first TMD of Rhbdf2 interacts with the TMD of ADAM17, and a point mutation (sinecure) in Rhbdf2 TMD1 blocks TNFα shedding. Structure-function analysis, structural modeling, mutagenesis, double-mutant mouse analysis Journal of Cell Science Medium 28104813
2017 The Uev1A-Ubc13 E2 ubiquitin-conjugating complex interacts with RHBDF2 and promotes K63-linked ubiquitination of RHBDF2 upon TNFα stimulation, enhancing its activity toward TACE maturation. Co-immunoprecipitation, ubiquitination assays, overexpression studies, TACE maturation assays Cellular Signalling Medium 29069608
2017 iRhom2 is required for innate immune signaling to RNA viruses by maintaining the stability of VISA (MAVS) through two distinct mechanisms: (1) mediating auto-ubiquitination and degradation of E3 ligase RNF5 to prevent ERAD of VISA, and (2) mediating proteasome-dependent degradation of E3 ligase MARCH5 to prevent mitochondria-associated degradation of VISA. iRhom2-deficient cells, viral infection assays, ubiquitination assays, co-immunoprecipitation, VISA stability assays PLoS Pathogens Medium 29155878
2020 The extracellular juxtamembrane domains (JMDs) of ADAM17 and iRhom2 regulate the stimulation and substrate selectivity of ADAM17; a non-activatable ADAM17 TMD mutant can only be rescued in cells containing iRhom, establishing that the ADAM17 TMD–iRhom2 TMD1 interaction is essential for substrate-selective shedding. ADAM17/iRhom2 domain swap and point mutants in Adam17-/- and iRhom1/2-/- cells, shedding assays FASEB Journal Medium 32103528
2020 ADAM17 stabilizes iRhom2 protein: endogenous iRhom2 is virtually undetectable in mEFs and bone marrow-derived macrophages lacking ADAM17, whereas iRhom1 levels are slightly increased in the absence of ADAM17, demonstrating that iRhom2 and ADAM17 are obligate binding partners with iRhom2 stability dependent on ADAM17. Cell surface biotinylation of endogenous proteins, Western blot in ADAM17-/- cells, comparison of iRhom1 and iRhom2 stability Journal of Biological Chemistry Medium 32060096
2021 TRIM31 directly binds Rhbdf2/iRhom2 and facilitates its proteasomal degradation; hepatocyte-specific TRIM31 ablation aggravates NAFLD phenotypes while TRIM31 gain-of-function alleviates steatohepatitis, identifying TRIM31 as an endogenous E3 ubiquitin ligase-mediated inhibitor of iRhom2. Co-immunoprecipitation, proteasomal degradation assays, hepatocyte-specific knockout and transgenic mice, ex vivo gene therapy Nature Communications Medium 35217669
2021 In response to high-fat diet, hepatic iRhom2 binds mitogen-activated protein kinase kinase kinase 7 (MAP3K7) to facilitate MAP3K7 phosphorylation and NF-κB cascade activation, promoting JNK/IRS-1 signaling and disturbing AKT/GSK3β-associated insulin signaling. Co-immunoprecipitation, phosphorylation assays, iRhom2 KO and myeloid-specific KO mice, bone marrow transplantation Hepatology Medium 32592194
2022 Oncogenic KRAS mutants target the cytoplasmic domain of iRhom2 to induce ADAM17-dependent shedding; activated ERK1/2 from oncogenic KRAS induces phosphorylation of iRhom2, recruitment of 14-3-3 proteins, and ADAM17-dependent shedding of ERBB ligands, placing iRhom2 as a central component of a positive feedback loop in lung cancer cells. Lung cancer cell lines, iRhom2 KO, phosphorylation assays, 14-3-3 recruitment, ERBB ligand shedding assays, tumor xenograft growth Journal of Cell Science Medium 35971826
2023 ZDHHC3 palmitoyltransferase catalyzes S-palmitoylation of iRhom2 at C476 in the iRhom homology domain (IRHD) via its DHHC (C157) domain; this palmitoylation facilitates iRhom2 cytomembrane translocation and stabilization, and blocks its ubiquitin-proteasome-related degradation mediated by TRIM31. S-palmitoylation assays, site-directed mutagenesis (C476), Co-IP, ZDHHC3 KO hepatocytes, in vivo mouse models Advanced Science Medium 37544908
2024 Cryo-EM structures of the human ADAM17/iRhom2 complex in inactive and active states reveal three mechanisms: (1) iRhom2 interacts with ADAM17 TMD to promote ADAM17 trafficking and maturation; (2) a unique iRhom2 extracellular domain retains the cleaved ADAM17 inhibitory prodomain to prevent premature activation; (3) loss of the prodomain from the complex mobilizes the ADAM17 protease domain to engage substrates. Cryo-electron microscopy structure determination, functional validation Molecular Cell High 38781971
2024 iRhom2 is a non-canonical substrate of the signal peptidase complex (SPC); SPC cleavage of iRhom2 generates an N-terminal fragment that enters the nucleus, modifies the transcriptome in part by binding C-terminal binding proteins (CtBPs), and promotes keratinocyte proliferation; nuclear iRhom2 levels are elevated in psoriasis and TOC patient skin biopsies. Biochemical cleavage assays, nuclear fractionation, co-immunoprecipitation with CtBPs, RNA-seq, patient skin biopsies Molecular Cell High 38183983
2024 iRhom2 contains a non-canonical, phosphorylation-independent 14-3-3 interaction site in its N-terminus that encompasses all known TOC mutations; disruption of this site dysregulates ADAM17 activity. The cub deletion also causes severe reductions in stimulated shedding, binding, and stability of ADAM17, whereas the TOC mutations affect ADAM17 function in a substrate-selective manner without substantially reducing mature ADAM17 levels. 14-3-3 binding assays, ADAM17 activity assays, mutagenesis of TOC and cub alleles, patient-derived cell comparison Cellular and Molecular Life Sciences Medium 38409522
2024 iRhom2 is a modifier of ADAM17-mediated TREM2 shedding in microglia; loss of iRhom2 increases TREM2 levels in cell lysates and at the cell surface and enhances TREM2 signaling and microglial phagocytosis of amyloid β-peptide. iRhom2-deficient BV2 cells, bone marrow-derived macrophages, primary murine microglia, TREM2 shedding assays, phagocytosis assays Life Science Alliance Medium 40081988
2025 Cryo-EM structure of the ADAM17 zymogen bound to iRhom2 reveals the interactions within the complex and the inhibitory mechanisms of the MEDI3622 antibody and ADAM17 prodomain; a membrane-proximal cytoplasmic reentry loop of iRhom2 is involved in the mechanism of ADAM17 activation. Cryo-EM structure determination, cellular functional validation assays PNAS High 40512800
2025 The iRhom2 cytoplasmic domain regulates ADAM17 by three distinct mechanisms: (1) RSK2 kinase is recruited to the iRhom2 N-terminus upon oncogenic KRAS signaling and coordinates with phospho-ERK to activate the iRhom2-ADAM17 sheddase complex; (2) stabilizing iRhom2 at the cell surface via its binding partner FRMD8 inhibits PMA-stimulated ADAM17 activity; (3) a defined RKR motif in the iRhom2 cytoplasmic domain represses unstimulated ADAM17 activity. Proteomic, genetic, and biochemical approaches; kinase recruitment assays; FRMD8 overexpression; RKR motif mutagenesis; ADAM17 activity assays Journal of Biological Chemistry Medium 40885391
2024 iRhom2 regulates ectodomain shedding and surface expression of MHC class I molecules in macrophages; iRhom2 loss reduces MHC-I shedding and surface expression, dampening autologous CD8+ T-cell activation and cytotoxicity in an EBV-transformed cell model. High-resolution proteomics on iRhom2-deficient murine and human macrophages, flow cytometry, CD8+ T-cell activation assays Cellular and Molecular Life Sciences Medium 38570362
2025 RHBDF2 interacts with STING in microglia and promotes activation of the STING-TBK1-IRF3/p65 signaling pathway; RHBDF2 knockdown alleviates neuroinflammation and brain injury in cerebral ischemia-reperfusion models by inhibiting this pathway. Additionally, the m6A reader YTHDF1 recognizes m6A sites on RHBDF2 mRNA and promotes RHBDF2 expression. Co-immunoprecipitation (RHBDF2-STING interaction), MCAO/R mouse model with microglia-specific RHBDF2 knockdown, methylated RNA immunoprecipitation, RNA-seq Molecular Medicine Medium 40898058
2014 iRhom2 is a target gene of the transcription factor p63; p63 and iRhom2 differentially regulate stress-associated signaling pathways in keratinocytes, with p63-iRhom2 modulating cell survival and response to oxidative stress via SURVIVIN and Cytoglobin. Reporter assays, ChIP for p63 binding to iRHOM2 locus, siRNA knockdown of iRhom2 in keratinocytes, stress assays Nature Communications Medium 29523849
2023 EGFR activation induces transcriptional upregulation of iRhom2, leading to increased surface localization of ADAM17 and ERK-mediated ADAM17 activity, resulting in proteolytic release of soluble IL-6 receptor (sIL-6R) to enable IL-6 trans-signaling in mammary epithelial cells. iRhom2 KD in epithelial cells, ADAM17 surface assays, sIL-6R release assays, ERK inhibition Biochimica et Biophysica Acta - Molecular Cell Research Medium 37271223

Source papers

Stage 0 corpus · 93 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 Alzheimer's disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci. Nature neuroscience 743 25129075
2012 Tumor necrosis factor signaling requires iRhom2 to promote trafficking and activation of TACE. Science (New York, N.Y.) 337 22246777
2012 iRhom2 regulation of TACE controls TNF-mediated protection against Listeria and responses to LPS. Science (New York, N.Y.) 273 22246778
2016 iRhom2 is essential for innate immunity to DNA viruses by mediating trafficking and stability of the adaptor STING. Nature immunology 224 27428826
2013 iRHOM2 is a critical pathogenic mediator of inflammatory arthritis. The Journal of clinical investigation 146 23348744
2013 iRhom2 controls the substrate selectivity of stimulated ADAM17-dependent ectodomain shedding. Proceedings of the National Academy of Sciences of the United States of America 141 23801765
2012 RHBDF2 mutations are associated with tylosis, a familial esophageal cancer syndrome. American journal of human genetics 138 22265016
2017 Phosphorylation of iRhom2 at the plasma membrane controls mammalian TACE-dependent inflammatory and growth factor signalling. eLife 91 28432785
2019 Reactive oxygen species-responsive dexamethasone-loaded nanoparticles for targeted treatment of rheumatoid arthritis via suppressing the iRhom2/TNF-α/BAFF signaling pathway. Biomaterials 90 31918224
2017 Phosphorylation of iRhom2 Controls Stimulated Proteolytic Shedding by the Metalloprotease ADAM17/TACE. Cell reports 88 29045841
2012 iRhom2 is required for the secretion of mouse TNFα. Blood 78 22550345
2018 iRhom2 promotes lupus nephritis through TNF-α and EGFR signaling. The Journal of clinical investigation 77 29369823
2014 iRHOM2-dependent regulation of ADAM17 in cutaneous disease and epidermal barrier function. Human molecular genetics 69 24643277
2018 iRhom2 loss alleviates renal injury in long-term PM2.5-exposed mice by suppression of inflammation and oxidative stress. Redox biology 66 30165303
2014 Rhbdf2 mutations increase its protein stability and drive EGFR hyperactivation through enhanced secretion of amphiregulin. Proceedings of the National Academy of Sciences of the United States of America 59 24825892
2015 Deletions in the cytoplasmic domain of iRhom1 and iRhom2 promote shedding of the TNF receptor by the protease ADAM17. Science signaling 52 26535007
2019 Endoplasmic reticulum stress-induced iRhom2 up-regulation promotes macrophage-regulated cardiac inflammation and lipid deposition in high fat diet (HFD)-challenged mice: Intervention of fisetin and metformin. Free radical biology & medicine 50 31153974
2018 Blood-induced bone loss in murine hemophilic arthropathy is prevented by blocking the iRhom2/ADAM17/TNF-α pathway. Blood 46 29776906
2017 iRhom2 is essential for innate immunity to RNA virus by antagonizing ER- and mitochondria-associated degradation of VISA. PLoS pathogens 42 29155878
2022 The E3 ubiquitin-protein ligase Trim31 alleviates non-alcoholic fatty liver disease by targeting Rhbdf2 in mouse hepatocytes. Nature communications 40 35217669
2012 Analysis of a Finnish family confirms RHBDF2 mutations as the underlying factor in tylosis with esophageal cancer. Familial cancer 40 22638770
2017 Total flavones of Abelmoschus manihot improve diabetic nephropathy by inhibiting the iRhom2/TACE signalling pathway activity in rats. Pharmaceutical biology 37 29221422
2017 Structural modeling defines transmembrane residues in ADAM17 that are crucial for Rhbdf2-ADAM17-dependent proteolysis. Journal of cell science 36 28104813
2018 Activated iRhom2 drives prolonged PM2.5 exposure-triggered renal injury in Nrf2-defective mice. Nanotoxicology 33 30257117
2017 iRhom2 deficiency relieves TNF-α associated hepatic dyslipidemia in long-term PM2.5-exposed mice. Biochemical and biophysical research communications 31 28965953
2014 Genetic interaction implicates iRhom2 in the regulation of EGF receptor signalling in mice. Biology open 30 25395669
2012 Chromosome 17q25 genes, RHBDF2 and CYGB, in ovarian cancer. International journal of oncology 30 22344671
2023 Palmitoyltransferase ZDHHC3 Aggravates Nonalcoholic Steatohepatitis by Targeting S-Palmitoylated IRHOM2. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 29 37544908
2021 ROS-mediated liposomal dexamethasone: a new FA-targeted nanoformulation to combat rheumatoid arthritis via inhibiting iRhom2/TNF-α/BAFF pathways. Nanoscale 28 34846489
2020 Substrate-selective protein ectodomain shedding by ADAM17 and iRhom2 depends on their juxtamembrane and transmembrane domains. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 28 32103528
2018 Role of iRhom2 in intestinal ischemia-reperfusion-mediated acute lung injury. Scientific reports 28 29491382
2021 Fisetin protects against high fat diet-induced nephropathy by inhibiting inflammation and oxidative stress via the blockage of iRhom2/NF-κB signaling. International immunopharmacology 27 33429334
2019 Deletion of iRhom2 protects against diet-induced obesity by increasing thermogenesis. Molecular metabolism 25 31918923
2019 Loss of RHBDF2 results in an early-onset spontaneous murine colitis. Journal of leukocyte biology 24 30694569
2018 p63 is a key regulator of iRHOM2 signalling in the keratinocyte stress response. Nature communications 24 29523849
2018 Multicombination Approach Suppresses Listeria monocytogenes-Induced Septicemia-Associated Acute Hepatic Failure: The Role of iRhom2 Signaling. Advanced healthcare materials 24 29944201
1996 Chromosomal localisation of the human envoplakin gene (EVPL) to the region of the tylosis oesophageal cancer gene (TOCG) on 17q25. Genomics 24 8938451
2022 Diosgenin inhibits ER stress-induced inflammation in aorta via iRhom2/TACE mediated signaling in experimental diabetic rats: An in vivo and in silico approach. Chemico-biological interactions 22 35305976
2020 ADAM17 stabilizes its interacting partner inactive Rhomboid 2 (iRhom2) but not inactive Rhomboid 1 (iRhom1). The Journal of biological chemistry 22 32060096
2020 iRhom2: An Emerging Adaptor Regulating Immunity and Disease. International journal of molecular sciences 22 32911849
2024 Cryo-EM reveals that iRhom2 restrains ADAM17 protease activity to control the release of growth factor and inflammatory signals. Molecular cell 21 38781971
2021 iRhom2 Promotes Hepatic Steatosis by Activating MAP3K7-Dependent Pathway. Hepatology (Baltimore, Md.) 21 32592194
2020 Loss of iRhom2 accelerates fat gain and insulin resistance in diet-induced obesity despite reduced adipose tissue inflammation. Metabolism: clinical and experimental 21 32135161
2017 Uev1A-Ubc13 catalyzes K63-linked ubiquitination of RHBDF2 to promote TACE maturation. Cellular signalling 20 29069608
2019 iRhom2 inhibits bile duct obstruction-induced liver fibrosis. Science signaling 19 31662486
2023 Single High-Dose Irradiation-Induced iRhom2 Upregulation Promotes Macrophage Antitumor Activity Through cGAS/STING Signaling. International journal of radiation oncology, biology, physics 17 36792017
2016 iRhom2 regulates CSF1R cell surface expression and non-steady state myelopoiesis in mice. European journal of immunology 16 27601030
2021 Congenital iRHOM2 deficiency causes ADAM17 dysfunction and environmentally directed immunodysregulatory disease. Nature immunology 15 34937930
2018 iRhom2-mediated proinflammatory signalling regulates heart repair following myocardial infarction. JCI insight 15 29415889
2018 iRhom2 promotes atherosclerosis through macrophage inflammation and induction of oxidative stress. Biochemical and biophysical research communications 15 30097271
2021 Inflammatory activation of surface molecule shedding by upregulation of the pseudoprotease iRhom2 in colon epithelial cells. Scientific reports 14 34930929
2016 iRhom2 is involved in lipopolysaccharide-induced cardiac injury in vivo and in vitro through regulating inflammation response. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 14 28033581
2015 Proteomic analysis of differentially expressed skin proteins in iRhom2(Uncv) mice. BMB reports 14 24667173
2014 iRhom2 mutation leads to aberrant hair follicle differentiation in mice. PloS one 14 25546423
2022 iRhom2 regulates ERBB signalling to promote KRAS-driven tumour growth of lung cancer cells. Journal of cell science 13 35971826
2017 Early induction of NRF2 antioxidant pathway by RHBDF2 mediates rapid cutaneous wound healing. Experimental and molecular pathology 13 28268192
2020 The iRhom2/ADAM17 Axis Attenuates Bacterial Uptake by Phagocytes in a Cell Autonomous Manner. International journal of molecular sciences 11 32825187
2020 Fenugreek attenuates obesity-induced inflammation and improves insulin resistance through downregulation of iRhom2/TACE. Life sciences 10 32768577
2018 RHBDF2-Regulated Growth Factor Signaling in a Rare Human Disease, Tylosis With Esophageal Cancer: What Can We Learn From Murine Models? Frontiers in genetics 10 30022999
2021 Inactive rhomboid proteins RHBDF1 and RHBDF2 (iRhoms): a decade of research in murine models. Mammalian genome : official journal of the International Mammalian Genome Society 9 34477920
2020 A genome-wide association study in mice reveals a role for Rhbdf2 in skeletal homeostasis. Scientific reports 9 32094386
2020 The Role of iRhom2 in Metabolic and Cardiovascular-Related Disorders. Frontiers in cardiovascular medicine 9 33330676
2024 Pathological mutations reveal the key role of the cytosolic iRhom2 N-terminus for phosphorylation-independent 14-3-3 interaction and ADAM17 binding, stability, and activity. Cellular and molecular life sciences : CMLS 8 38409522
2020 iRHOM2: A Regulator of Palmoplantar Biology, Inflammation, and Viral Susceptibility. The Journal of investigative dermatology 8 33080304
2024 Cleavage of the pseudoprotease iRhom2 by the signal peptidase complex reveals an ER-to-nucleus signaling pathway. Molecular cell 7 38183983
2024 iRhom2 regulates ectodomain shedding and surface expression of the major histocompatibility complex (MHC) class I. Cellular and molecular life sciences : CMLS 7 38570362
2023 EGFR stimulation enables IL-6 trans-signalling via iRhom2-dependent ADAM17 activation in mammary epithelial cells. Biochimica et biophysica acta. Molecular cell research 7 37271223
2022 Deficiency of inactive rhomboid protein 2 (iRhom2) attenuates diet-induced hyperlipidaemia and early atherogenesis. Cardiovascular research 7 33576385
2019 iRhom2 and TNF: Partners or enemies? Science signaling 7 31662485
2018 Collagen-Induced Arthritis Analysis in Rhbdf2 Knockout Mouse. Biomolecules & therapeutics 7 29223140
2023 Analysis of the function of ADAM17 in iRhom2 curly-bare and tylosis with esophageal cancer mutant mice. Journal of cell science 6 37282854
2021 The Threshold Effect: Lipopolysaccharide-Induced Inflammatory Responses in Primary Macrophages Are Differentially Regulated in an iRhom2-Dependent Manner. Frontiers in cellular and infection microbiology 6 33585287
2021 RHBDF2 gene functions are correlated to facilitated renal clear cell carcinoma progression. Cancer cell international 6 34736454
2025 RHBDF2 governs microglial neuroinflammation during cerebral ischemia-reperfusion injury and is positively regulated by the m6A reader YTHDF1. Molecular medicine (Cambridge, Mass.) 5 40898058
2023 Mechanistic insight on the role of iRhom2-TNF-α-BAFF signaling pathway in various autoimmune disorders. Advances in biological regulation 5 38151421
2022 Deficiency in Inactive Rhomboid Protein2 (iRhom2) Alleviates Alcoholic Liver Fibrosis by Suppressing Inflammation and Oxidative Stress. International journal of molecular sciences 5 35887045
2020 4-Hydroxyisoleucine relieves inflammation through iRhom2-dependent pathway in co-cultured macrophages and adipocytes with LPS stimulation. BMC complementary medicine and therapies 5 33298044
2017 Tissue-specific role of RHBDF2 in cutaneous wound healing and hyperproliferative skin disease. BMC research notes 5 29116018
2025 The late-onset Alzheimer's disease risk factor RHBDF2 is a modifier of microglial TREM2 proteolysis. Life science alliance 4 40081988
2020 iRhom2 in the pathogenesis of oral squamous cell carcinoma. Molecular biology reports 4 32236893
2025 Structural insights into the activation and inhibition of the ADAM17-iRhom2 complex. Proceedings of the National Academy of Sciences of the United States of America 3 40512800
2016 iRhom2 (Uncv) mutation blocks bulge stem cells assuming the fate of hair follicle. Archives of dermatological research 3 27393687
2015 3D Structure Generation, Molecular Dynamics and Docking Studies of IRHOM2 Protein Involved in Cancer & Rheumatoid Arthritis. Current computer-aided drug design 3 26603928
2022 Investigating isoform switching in RHBDF2 and its role in neoplastic growth in breast cancer. PeerJ 2 36452073
2024 Role of iRhom2 in Olfaction: Implications for Odorant Receptor Regulation and Activity-Dependent Adaptation. International journal of molecular sciences 1 38892263
2024 iRhom2 deficiency reduces sepsis-induced mortality associated with the attenuation of lung macrophages in mice. Histochemistry and cell biology 1 39134731
2024 Targeting iRhom2/ADAM17 attenuates COVID-19-induced cytokine release from cultured lung epithelial cells. Biochemistry and biophysics reports 1 39253056
2023 RHBDF2 is correlated with immune infiltrates in hepatocellular carcinoma and may have potential as a biomarker. FEBS open bio 1 36943228
2023 iRHOM2 regulates inflammation and endothelial barrier permeability via CX3CL1. Experimental and therapeutic medicine 1 37273752
2026 iRhom2 regulates HMGB1 secretion to modulate inflammation and hepatocyte senescence in an in vitro model of ischemia-reperfusion injury. Cell death & disease 0 41501003
2026 iRhom2 deletion protects against diabetic neuropathy by suppressing neuroinflammation. The Journal of pharmacology and experimental therapeutics 0 41666516
2025 The cytoplasmic domain of the pseudoprotease iRhom2 mediates distinct signaling mechanisms to control activation of the cell surface protease ADAM17. The Journal of biological chemistry 0 40885391
2023 Investigating iRHOM2-Associated Transcriptional Changes in Tylosis With Esophageal Cancer. Gastro hep advances 0 39131151

Missed literature

Know a paper Affinage missed for RHBDF2? Flag it for the maintainers and the community.

No submissions yet.