{"gene":"RHBDF2","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":2012,"finding":"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.","method":"Mouse knockout, co-immunoprecipitation, subcellular fractionation, TNF shedding assays","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal findings replicated in two independent simultaneous papers (PMID:22246777 and PMID:22246778) using KO mice, Co-IP, and functional shedding assays","pmids":["22246777","22246778"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Gene-targeted iRhom2-deficient mice, co-immunoprecipitation, TNFα shedding assays, infection models","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — replicated across two independent labs simultaneously (PMID:22246777, PMID:22246778), KO mice with defined cellular phenotype","pmids":["22246778","22246777"],"is_preprint":false},{"year":2012,"finding":"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.","method":"ENU-induced missense mutation in mice, cytokine secretion assays in macrophages","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single lab, genetic mutation with specific functional readout distinguishing TNFα from IL-6","pmids":["22550345"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Targeted capture sequencing, immortalized patient keratinocytes, immunohistochemistry, proliferation and migration assays","journal":"American Journal of Human Genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — disease-causing mutations identified by sequencing and functionally validated in patient-derived cells, replicated in additional families (PMID:22638770)","pmids":["22265016","22638770"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Rhbdf2-deficient mouse models, K/BxN inflammatory arthritis model, TNF shedding assays in mouse and human cells","journal":"Journal of Clinical Investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple mouse models, epistasis with TACE and TNFa KO, tissue-specific functional dissection","pmids":["23348744"],"is_preprint":false},{"year":2013,"finding":"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.","method":"iRhom2-/- mouse embryonic fibroblasts, shedding assays, siRNA knockdown, rescue with wild-type vs. deletion constructs","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — domain mutagenesis with rescue, multiple substrates tested, single lab with multiple orthogonal methods","pmids":["23801765"],"is_preprint":false},{"year":2014,"finding":"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.","method":"TOC patient-derived keratinocytes, ADAM17 activity assays, Western blotting, immunostaining","journal":"Human Molecular Genetics","confidence":"High","confidence_rationale":"Tier 2 / Moderate — patient-derived tissues, multiple functional readouts, single lab","pmids":["24643277"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Mouse models with N-terminal iRhom2 mutations, amphiregulin secretion assays, wound healing assays, in vivo tumor models","journal":"PNAS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mouse models and biochemical assays, single lab","pmids":["24825892"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Genetic screen, fibrosarcoma cell lines with iRhom-ΔN constructs, ADAM17 inhibitors, TOC patient keratinocytes","journal":"Science Signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic screen plus domain deletions and patient cells, single lab","pmids":["26535007"],"is_preprint":false},{"year":2016,"finding":"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.","method":"iRhom2-deficient cells and mice, co-immunoprecipitation, viral infection assays, ubiquitination assays, HSV-1 challenge","journal":"Nature Immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, ubiquitination assays, KO mice with survival readout), two distinct mechanisms defined","pmids":["27428826"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Mixed bone marrow chimeras, degradomics screen, flow cytometry, in vitro CSF1 response assays","journal":"European Journal of Immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — unbiased proteomics screen plus KO mouse functional assay, single lab","pmids":["27601030"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Co-immunoprecipitation, phosphorylation assays, 14-3-3 binding assays, primary macrophage TNF shedding assays, cell surface biotinylation","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, phosphorylation, 14-3-3 binding, functional shedding in primary cells), consistent with independent paper (PMID:29045841)","pmids":["28432785"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Phosphoproteomics, 14-3-3 binding assays, co-immunoprecipitation, shedding assays","journal":"Cell Reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — proteomic plus biochemical confirmation of phosphorylation-14-3-3 mechanism, independently replicated in PMID:28432785","pmids":["29045841"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Structure-function analysis, structural modeling, mutagenesis, double-mutant mouse analysis","journal":"Journal of Cell Science","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — structural modeling combined with in vivo mutagenesis, single lab","pmids":["28104813"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Co-immunoprecipitation, ubiquitination assays, overexpression studies, TACE maturation assays","journal":"Cellular Signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP and ubiquitination assays, single lab, single paper","pmids":["29069608"],"is_preprint":false},{"year":2017,"finding":"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.","method":"iRhom2-deficient cells, viral infection assays, ubiquitination assays, co-immunoprecipitation, VISA stability assays","journal":"PLoS Pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods, single lab, distinct mechanisms defined","pmids":["29155878"],"is_preprint":false},{"year":2020,"finding":"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.","method":"ADAM17/iRhom2 domain swap and point mutants in Adam17-/- and iRhom1/2-/- cells, shedding assays","journal":"FASEB Journal","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — domain mutagenesis with functional rescue, multiple cell lines, single lab","pmids":["32103528"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Cell surface biotinylation of endogenous proteins, Western blot in ADAM17-/- cells, comparison of iRhom1 and iRhom2 stability","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — endogenous protein analysis, multiple cell types, single lab","pmids":["32060096"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Co-immunoprecipitation, proteasomal degradation assays, hepatocyte-specific knockout and transgenic mice, ex vivo gene therapy","journal":"Nature Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding demonstrated, in vivo KO and gain-of-function, single lab","pmids":["35217669"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Co-immunoprecipitation, phosphorylation assays, iRhom2 KO and myeloid-specific KO mice, bone marrow transplantation","journal":"Hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus in vivo KO models and bone marrow transfer, single lab","pmids":["32592194"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Lung cancer cell lines, iRhom2 KO, phosphorylation assays, 14-3-3 recruitment, ERBB ligand shedding assays, tumor xenograft growth","journal":"Journal of Cell Science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays plus in vivo xenograft, single lab","pmids":["35971826"],"is_preprint":false},{"year":2023,"finding":"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.","method":"S-palmitoylation assays, site-directed mutagenesis (C476), Co-IP, ZDHHC3 KO hepatocytes, in vivo mouse models","journal":"Advanced Science","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — palmitoylation site mutagenesis and enzyme identification, in vivo and in vitro, single lab","pmids":["37544908"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Cryo-electron microscopy structure determination, functional validation","journal":"Molecular Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structures of both inactive and active states with functional validation, reveals three distinct regulatory mechanisms","pmids":["38781971"],"is_preprint":false},{"year":2024,"finding":"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.","method":"Biochemical cleavage assays, nuclear fractionation, co-immunoprecipitation with CtBPs, RNA-seq, patient skin biopsies","journal":"Molecular Cell","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — SPC cleavage demonstrated biochemically, nuclear localization and CtBP binding established, multiple orthogonal methods in one study","pmids":["38183983"],"is_preprint":false},{"year":2024,"finding":"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.","method":"14-3-3 binding assays, ADAM17 activity assays, mutagenesis of TOC and cub alleles, patient-derived cell comparison","journal":"Cellular and Molecular Life Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mutagenesis with functional readouts, multiple mutations compared, single lab","pmids":["38409522"],"is_preprint":false},{"year":2024,"finding":"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.","method":"iRhom2-deficient BV2 cells, bone marrow-derived macrophages, primary murine microglia, TREM2 shedding assays, phagocytosis assays","journal":"Life Science Alliance","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple cell types including primary microglia, multiple functional assays, single lab","pmids":["40081988"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Cryo-EM structure determination, cellular functional validation assays","journal":"PNAS","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structure with cellular functional validation, independent of PMID:38781971, revealing additional regulatory elements","pmids":["40512800"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Proteomic, genetic, and biochemical approaches; kinase recruitment assays; FRMD8 overexpression; RKR motif mutagenesis; ADAM17 activity assays","journal":"Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — three mechanisms from proteomic and biochemical approaches, single lab, single paper","pmids":["40885391"],"is_preprint":false},{"year":2024,"finding":"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.","method":"High-resolution proteomics on iRhom2-deficient murine and human macrophages, flow cytometry, CD8+ T-cell activation assays","journal":"Cellular and Molecular Life Sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics plus functional immune assay, both murine and human cells, single lab","pmids":["38570362"],"is_preprint":false},{"year":2025,"finding":"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.","method":"Co-immunoprecipitation (RHBDF2-STING interaction), MCAO/R mouse model with microglia-specific RHBDF2 knockdown, methylated RNA immunoprecipitation, RNA-seq","journal":"Molecular Medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, in vivo KO with defined phenotype, multiple methods, single lab","pmids":["40898058"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Reporter assays, ChIP for p63 binding to iRHOM2 locus, siRNA knockdown of iRhom2 in keratinocytes, stress assays","journal":"Nature Communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transcription factor binding demonstrated plus functional downstream assays, single lab","pmids":["29523849"],"is_preprint":false},{"year":2023,"finding":"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.","method":"iRhom2 KD in epithelial cells, ADAM17 surface assays, sIL-6R release assays, ERK inhibition","journal":"Biochimica et Biophysica Acta - Molecular Cell Research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional knockdown with mechanistic dissection, single lab","pmids":["37271223"],"is_preprint":false}],"current_model":"iRhom2 (RHBDF2) is a catalytically inactive, seven-transmembrane rhomboid pseudoprotease that functions as a multifunctional regulatory cofactor of the metalloprotease ADAM17/TACE: it binds ADAM17 throughout the secretory pathway to mediate its ER exit, furin-mediated maturation, and trafficking to the cell surface; a unique extracellular domain retains the cleaved ADAM17 prodomain to prevent premature activation; ERK1/2-mediated phosphorylation of its cytoplasmic N-terminus (further regulated by RSK2, 14-3-3 proteins, FRMD8, and an intrinsic RKR repressor motif) licenses ADAM17 catalytic activity at the plasma membrane to control stimulated, substrate-selective shedding of TNFα, EGFR ligands, TNF receptors, CSF1R, MHC-I, and other substrates; iRhom2 stability itself depends on ADAM17 binding, and is regulated by S-palmitoylation (by ZDHHC3 at C476) and proteasomal degradation (by TRIM31); independent of ADAM17, iRhom2 regulates innate antiviral immunity by associating with STING and VISA/MAVS to control their trafficking and stability, and an SPC-cleaved N-terminal fragment of iRhom2 translocates to the nucleus where it binds CtBPs to modify the transcriptome and promote keratinocyte proliferation."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2012,"claim":"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","pmids":["22246777","22246778"],"confidence":"High","gaps":["Did not define the structural basis of the iRhom2-ADAM17 interaction","Mechanism of activation versus trafficking not separated"]},{"year":2012,"claim":"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","pmids":["22550345"],"confidence":"Medium","gaps":["Did not map the affected residue to a mechanistic step","Single lab"]},{"year":2012,"claim":"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","pmids":["22265016","22638770"],"confidence":"High","gaps":["Did not establish whether mutations were gain- or loss-of-function at the time","Link between EGFR changes and ADAM17 not yet mechanistic"]},{"year":2013,"claim":"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","pmids":["23348744","23801765"],"confidence":"High","gaps":["Did not define how the cytoplasmic domain selects substrates","Signaling inputs to the domain unknown"]},{"year":2014,"claim":"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","pmids":["24643277","24825892"],"confidence":"High","gaps":["Reported partly ADAM17-independent amphiregulin effects without a defined alternative mechanism","Single lab for each model"]},{"year":2014,"claim":"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","pmids":["29523849"],"confidence":"Medium","gaps":["Did not connect transcriptional regulation to ADAM17 activity","Single lab"]},{"year":2015,"claim":"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","pmids":["26535007"],"confidence":"Medium","gaps":["Did not establish in vivo relevance of TNFR shedding","Single lab"]},{"year":2016,"claim":"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)","pmids":["27428826"],"confidence":"High","gaps":["Did not reconcile pseudoprotease iRhom2 acting outside the secretory/ADAM17 axis structurally","Direct vs. indirect recruitment of cofactors not fully resolved"]},{"year":2016,"claim":"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","pmids":["27601030"],"confidence":"Medium","gaps":["Did not establish physiological consequences beyond competitive repopulation","Single lab"]},{"year":2017,"claim":"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","pmids":["28432785","29045841"],"confidence":"High","gaps":["Did not identify all kinases and adaptors feeding the switch","Structural consequence of dissociation not visualized"]},{"year":2017,"claim":"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","pmids":["28104813"],"confidence":"Medium","gaps":["Modeling-based rather than experimental structure","Single lab"]},{"year":2017,"claim":"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","pmids":["29069608"],"confidence":"Medium","gaps":["Largely overexpression-based without in vivo confirmation","Ubiquitination site not defined"]},{"year":2017,"claim":"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","pmids":["29155878"],"confidence":"Medium","gaps":["Mechanism of selective E3-ligase degradation not fully resolved","Single lab"]},{"year":2020,"claim":"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","pmids":["32060096","32103528"],"confidence":"Medium","gaps":["Did not yet provide an experimental structure","Substrate-selection code not fully decoded"]},{"year":2021,"claim":"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","pmids":["35217669","32592194"],"confidence":"Medium","gaps":["MAP3K7 binding role versus canonical ADAM17 function not fully separated","Single lab per finding"]},{"year":2022,"claim":"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","pmids":["35971826"],"confidence":"Medium","gaps":["Did not define which ERK-dependent residues are KRAS-specific","Single lab"]},{"year":2023,"claim":"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","pmids":["37544908"],"confidence":"Medium","gaps":["Did not establish how palmitoylation intersects with the activation switch","Single lab"]},{"year":2023,"claim":"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","pmids":["37271223"],"confidence":"Medium","gaps":["Did not define the transcription factor mediating EGFR-driven induction","Single lab"]},{"year":2024,"claim":"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","pmids":["38781971"],"confidence":"High","gaps":["Did not resolve cytoplasmic activation elements at high resolution","Dynamics of prodomain release not directly observed"]},{"year":2024,"claim":"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","pmids":["38183983"],"confidence":"High","gaps":["Did not define the nuclear fragment's direct DNA/chromatin targets","Relationship to membrane-bound iRhom2 pool unclear"]},{"year":2024,"claim":"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","pmids":["38409522"],"confidence":"Medium","gaps":["Did not structurally resolve the non-canonical 14-3-3 site","Single lab"]},{"year":2024,"claim":"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","pmids":["38570362","40081988"],"confidence":"Medium","gaps":["Did not establish in vivo consequences in neurodegeneration or anti-tumor immunity","Single lab per finding"]},{"year":2025,"claim":"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","pmids":["40512800"],"confidence":"High","gaps":["Did not capture the fully activated, substrate-engaged state dynamics","Cytoplasmic switch elements only partly resolved"]},{"year":2025,"claim":"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","pmids":["40885391"],"confidence":"Medium","gaps":["Did not define how the three mechanisms are temporally coordinated","Single lab"]},{"year":2025,"claim":"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","pmids":["40898058"],"confidence":"Medium","gaps":["Did not separate STING-pathway effects from ADAM17-dependent functions","Single lab"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,4,5,11,22,27]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,9,15,22]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[22,26]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,9]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,11,17,21]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[23]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[15]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,2,4,9,15,28]},{"term_id":"R-HSA-392499","term_label":"Metabolism of 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METALLOPROTEINASE DOMAIN 17; ADAM17","url":"https://www.omim.org/entry/603639"},{"mim_id":"148500","title":"TYLOSIS WITH ESOPHAGEAL CANCER; TOC","url":"https://www.omim.org/entry/148500"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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co-immunoprecipitation, subcellular fractionation, TNF shedding assays\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal findings replicated in two independent simultaneous papers (PMID:22246777 and PMID:22246778) using KO mice, Co-IP, and functional shedding assays\",\n      \"pmids\": [\"22246777\", \"22246778\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Gene-targeted iRhom2-deficient mice, co-immunoprecipitation, TNFα shedding assays, infection models\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — replicated across two independent labs simultaneously (PMID:22246777, PMID:22246778), KO mice with defined cellular phenotype\",\n      \"pmids\": [\"22246778\", \"22246777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"ENU-induced missense mutation in mice, cytokine secretion assays in macrophages\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single lab, genetic mutation with specific functional readout distinguishing TNFα from IL-6\",\n      \"pmids\": [\"22550345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Targeted capture sequencing, immortalized patient keratinocytes, immunohistochemistry, proliferation and migration assays\",\n      \"journal\": \"American Journal of Human Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — disease-causing mutations identified by sequencing and functionally validated in patient-derived cells, replicated in additional families (PMID:22638770)\",\n      \"pmids\": [\"22265016\", \"22638770\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Rhbdf2-deficient mouse models, K/BxN inflammatory arthritis model, TNF shedding assays in mouse and human cells\",\n      \"journal\": \"Journal of Clinical Investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple mouse models, epistasis with TACE and TNFa KO, tissue-specific functional dissection\",\n      \"pmids\": [\"23348744\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"iRhom2-/- mouse embryonic fibroblasts, shedding assays, siRNA knockdown, rescue with wild-type vs. deletion constructs\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — domain mutagenesis with rescue, multiple substrates tested, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"23801765\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"TOC patient-derived keratinocytes, ADAM17 activity assays, Western blotting, immunostaining\",\n      \"journal\": \"Human Molecular Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient-derived tissues, multiple functional readouts, single lab\",\n      \"pmids\": [\"24643277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Mouse models with N-terminal iRhom2 mutations, amphiregulin secretion assays, wound healing assays, in vivo tumor models\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse models and biochemical assays, single lab\",\n      \"pmids\": [\"24825892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Genetic screen, fibrosarcoma cell lines with iRhom-ΔN constructs, ADAM17 inhibitors, TOC patient keratinocytes\",\n      \"journal\": \"Science Signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic screen plus domain deletions and patient cells, single lab\",\n      \"pmids\": [\"26535007\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"iRhom2-deficient cells and mice, co-immunoprecipitation, viral infection assays, ubiquitination assays, HSV-1 challenge\",\n      \"journal\": \"Nature Immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, ubiquitination assays, KO mice with survival readout), two distinct mechanisms defined\",\n      \"pmids\": [\"27428826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Mixed bone marrow chimeras, degradomics screen, flow cytometry, in vitro CSF1 response assays\",\n      \"journal\": \"European Journal of Immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — unbiased proteomics screen plus KO mouse functional assay, single lab\",\n      \"pmids\": [\"27601030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation assays, 14-3-3 binding assays, primary macrophage TNF shedding assays, cell surface biotinylation\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, phosphorylation, 14-3-3 binding, functional shedding in primary cells), consistent with independent paper (PMID:29045841)\",\n      \"pmids\": [\"28432785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Phosphoproteomics, 14-3-3 binding assays, co-immunoprecipitation, shedding assays\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — proteomic plus biochemical confirmation of phosphorylation-14-3-3 mechanism, independently replicated in PMID:28432785\",\n      \"pmids\": [\"29045841\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Structure-function analysis, structural modeling, mutagenesis, double-mutant mouse analysis\",\n      \"journal\": \"Journal of Cell Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — structural modeling combined with in vivo mutagenesis, single lab\",\n      \"pmids\": [\"28104813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, overexpression studies, TACE maturation assays\",\n      \"journal\": \"Cellular Signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP and ubiquitination assays, single lab, single paper\",\n      \"pmids\": [\"29069608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"iRhom2-deficient cells, viral infection assays, ubiquitination assays, co-immunoprecipitation, VISA stability assays\",\n      \"journal\": \"PLoS Pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods, single lab, distinct mechanisms defined\",\n      \"pmids\": [\"29155878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"ADAM17/iRhom2 domain swap and point mutants in Adam17-/- and iRhom1/2-/- cells, shedding assays\",\n      \"journal\": \"FASEB Journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — domain mutagenesis with functional rescue, multiple cell lines, single lab\",\n      \"pmids\": [\"32103528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Cell surface biotinylation of endogenous proteins, Western blot in ADAM17-/- cells, comparison of iRhom1 and iRhom2 stability\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — endogenous protein analysis, multiple cell types, single lab\",\n      \"pmids\": [\"32060096\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, proteasomal degradation assays, hepatocyte-specific knockout and transgenic mice, ex vivo gene therapy\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding demonstrated, in vivo KO and gain-of-function, single lab\",\n      \"pmids\": [\"35217669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, phosphorylation assays, iRhom2 KO and myeloid-specific KO mice, bone marrow transplantation\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus in vivo KO models and bone marrow transfer, single lab\",\n      \"pmids\": [\"32592194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Lung cancer cell lines, iRhom2 KO, phosphorylation assays, 14-3-3 recruitment, ERBB ligand shedding assays, tumor xenograft growth\",\n      \"journal\": \"Journal of Cell Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays plus in vivo xenograft, single lab\",\n      \"pmids\": [\"35971826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"S-palmitoylation assays, site-directed mutagenesis (C476), Co-IP, ZDHHC3 KO hepatocytes, in vivo mouse models\",\n      \"journal\": \"Advanced Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — palmitoylation site mutagenesis and enzyme identification, in vivo and in vitro, single lab\",\n      \"pmids\": [\"37544908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Cryo-electron microscopy structure determination, functional validation\",\n      \"journal\": \"Molecular Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structures of both inactive and active states with functional validation, reveals three distinct regulatory mechanisms\",\n      \"pmids\": [\"38781971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"Biochemical cleavage assays, nuclear fractionation, co-immunoprecipitation with CtBPs, RNA-seq, patient skin biopsies\",\n      \"journal\": \"Molecular Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — SPC cleavage demonstrated biochemically, nuclear localization and CtBP binding established, multiple orthogonal methods in one study\",\n      \"pmids\": [\"38183983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"14-3-3 binding assays, ADAM17 activity assays, mutagenesis of TOC and cub alleles, patient-derived cell comparison\",\n      \"journal\": \"Cellular and Molecular Life Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mutagenesis with functional readouts, multiple mutations compared, single lab\",\n      \"pmids\": [\"38409522\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"iRhom2-deficient BV2 cells, bone marrow-derived macrophages, primary murine microglia, TREM2 shedding assays, phagocytosis assays\",\n      \"journal\": \"Life Science Alliance\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple cell types including primary microglia, multiple functional assays, single lab\",\n      \"pmids\": [\"40081988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Cryo-EM structure determination, cellular functional validation assays\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structure with cellular functional validation, independent of PMID:38781971, revealing additional regulatory elements\",\n      \"pmids\": [\"40512800\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Proteomic, genetic, and biochemical approaches; kinase recruitment assays; FRMD8 overexpression; RKR motif mutagenesis; ADAM17 activity assays\",\n      \"journal\": \"Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — three mechanisms from proteomic and biochemical approaches, single lab, single paper\",\n      \"pmids\": [\"40885391\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"High-resolution proteomics on iRhom2-deficient murine and human macrophages, flow cytometry, CD8+ T-cell activation assays\",\n      \"journal\": \"Cellular and Molecular Life Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics plus functional immune assay, both murine and human cells, single lab\",\n      \"pmids\": [\"38570362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation (RHBDF2-STING interaction), MCAO/R mouse model with microglia-specific RHBDF2 knockdown, methylated RNA immunoprecipitation, RNA-seq\",\n      \"journal\": \"Molecular Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, in vivo KO with defined phenotype, multiple methods, single lab\",\n      \"pmids\": [\"40898058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Reporter assays, ChIP for p63 binding to iRHOM2 locus, siRNA knockdown of iRhom2 in keratinocytes, stress assays\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transcription factor binding demonstrated plus functional downstream assays, single lab\",\n      \"pmids\": [\"29523849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"iRhom2 KD in epithelial cells, ADAM17 surface assays, sIL-6R release assays, ERK inhibition\",\n      \"journal\": \"Biochimica et Biophysica Acta - Molecular Cell Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional knockdown with mechanistic dissection, single lab\",\n      \"pmids\": [\"37271223\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"iRhom2 (RHBDF2) is a catalytically inactive, seven-transmembrane rhomboid pseudoprotease that functions as a multifunctional regulatory cofactor of the metalloprotease ADAM17/TACE: it binds ADAM17 throughout the secretory pathway to mediate its ER exit, furin-mediated maturation, and trafficking to the cell surface; a unique extracellular domain retains the cleaved ADAM17 prodomain to prevent premature activation; ERK1/2-mediated phosphorylation of its cytoplasmic N-terminus (further regulated by RSK2, 14-3-3 proteins, FRMD8, and an intrinsic RKR repressor motif) licenses ADAM17 catalytic activity at the plasma membrane to control stimulated, substrate-selective shedding of TNFα, EGFR ligands, TNF receptors, CSF1R, MHC-I, and other substrates; iRhom2 stability itself depends on ADAM17 binding, and is regulated by S-palmitoylation (by ZDHHC3 at C476) and proteasomal degradation (by TRIM31); independent of ADAM17, iRhom2 regulates innate antiviral immunity by associating with STING and VISA/MAVS to control their trafficking and stability, and an SPC-cleaved N-terminal fragment of iRhom2 translocates to the nucleus where it binds CtBPs to modify the transcriptome and promote keratinocyte proliferation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #22]. iRhom2 binds nascent ADAM17 in the ER and is required for its exit, furin-mediated maturation, and trafficking to the cell surface, controlling TNF\\u03b1 shedding in hematopoietic and immune cells in a tissue-selective manner distinct from its paralog iRhom1 [#0, #1, #4]. 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 [#13, #22, #26]. The interaction is reciprocally stabilizing\\u2014iRhom2 stability depends on ADAM17 binding [#17]. 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 [#11, #12, #27]. Through ADAM17, iRhom2 governs substrate-selective shedding of TNF\\u03b1, EGF-family ligands, TNF receptors, CSF1R, MHC class I, and TREM2, coupling it to inflammation, EGFR signaling, and myeloid biology [#5, #8, #10, #25, #28]. 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 [#3, #6, #7]. Independent of ADAM17, iRhom2 supports innate antiviral immunity by stabilizing and trafficking STING and VISA/MAVS [#9, #15], and an SPC-cleaved N-terminal fragment translocates to the nucleus to bind CtBPs and reprogram the keratinocyte transcriptome [#23].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"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 TNF\\u03b1 shedding.\",\n      \"evidence\": \"Knockout mice, co-immunoprecipitation, subcellular fractionation, and TNF shedding assays, replicated across two simultaneous papers\",\n      \"pmids\": [\"22246777\", \"22246778\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the structural basis of the iRhom2-ADAM17 interaction\", \"Mechanism of activation versus trafficking not separated\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Showed iRhom2's role in TNF\\u03b1 release is specific and selective downstream of Toll-like receptors, not a general secretory defect.\",\n      \"evidence\": \"ENU-induced missense mutation in mice with cytokine secretion assays distinguishing TNF\\u03b1 from IL-6 in macrophages\",\n      \"pmids\": [\"22550345\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not map the affected residue to a mechanistic step\", \"Single lab\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connected iRhom2 to human disease, establishing N-terminal cytoplasmic-domain missense mutations as the cause of Tylosis with Esophageal Cancer with dysregulated EGFR signaling.\",\n      \"evidence\": \"Targeted capture sequencing and patient-derived keratinocyte proliferation/migration assays, replicated in additional families\",\n      \"pmids\": [\"22265016\", \"22638770\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish whether mutations were gain- or loss-of-function at the time\", \"Link between EGFR changes and ADAM17 not yet mechanistic\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"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.\",\n      \"evidence\": \"Rhbdf2-deficient mouse models, arthritis models, and iRhom2 domain-deletion rescue in MEFs with multiple substrates\",\n      \"pmids\": [\"23348744\", \"23801765\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define how the cytoplasmic domain selects substrates\", \"Signaling inputs to the domain unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"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.\",\n      \"evidence\": \"TOC patient keratinocytes and mouse N-terminal-mutant models with ADAM17 activity, amphiregulin secretion, and in vivo tumor/wound assays\",\n      \"pmids\": [\"24643277\", \"24825892\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reported partly ADAM17-independent amphiregulin effects without a defined alternative mechanism\", \"Single lab for each model\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified upstream transcriptional control, placing iRhom2 as a p63 target gene linking it to keratinocyte stress and survival responses.\",\n      \"evidence\": \"Reporter assays, ChIP for p63 binding, and iRhom2 knockdown with oxidative stress readouts in keratinocytes\",\n      \"pmids\": [\"29523849\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not connect transcriptional regulation to ADAM17 activity\", \"Single lab\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Linked iRhom2 to TNF-receptor biology by showing N-terminal deletions increase ADAM17 activity and TNFR shedding, conferring resistance to TNF-induced cell death.\",\n      \"evidence\": \"Genetic screen with iRhom-\\u0394N constructs, ADAM17 inhibitors, and TOC patient keratinocytes\",\n      \"pmids\": [\"26535007\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not establish in vivo relevance of TNFR shedding\", \"Single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Revealed an ADAM17-independent role in innate antiviral immunity, with iRhom2 controlling STING trafficking and stability against DNA viruses.\",\n      \"evidence\": \"iRhom2-deficient cells and mice, Co-IP, ubiquitination assays, and HSV-1 challenge defining two distinct mechanisms (TRAP\\u03b2 recruitment and EIF3S5 deubiquitination)\",\n      \"pmids\": [\"27428826\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not reconcile pseudoprotease iRhom2 acting outside the secretory/ADAM17 axis structurally\", \"Direct vs. indirect recruitment of cofactors not fully resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extended the ADAM17-substrate repertoire to CSF1R, linking iRhom2 to myeloid surface-receptor levels and progenitor competitiveness.\",\n      \"evidence\": \"Mixed bone marrow chimeras, degradomics screen, and flow cytometry in iRhom2-/- mice\",\n      \"pmids\": [\"27601030\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not establish physiological consequences beyond competitive repopulation\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined the activation switch: phosphorylation of the iRhom2 N-terminus and 14-3-3 recruitment dissociate ADAM17 from iRhom2 to license surface shedding.\",\n      \"evidence\": \"Co-IP, phosphorylation/phosphoproteomics, 14-3-3 binding, and primary macrophage shedding assays, independently replicated across two papers\",\n      \"pmids\": [\"28432785\", \"29045841\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify all kinases and adaptors feeding the switch\", \"Structural consequence of dissociation not visualized\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Mapped the physical TMD interface, showing iRhom2 TMD1 contacts the ADAM17 TMD and that this contact is required for TNF\\u03b1 shedding.\",\n      \"evidence\": \"Structural modeling, mutagenesis (sinecure allele), and double-mutant mouse analysis\",\n      \"pmids\": [\"28104813\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Modeling-based rather than experimental structure\", \"Single lab\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified post-translational positive regulation, with Uev1A-Ubc13 promoting K63-linked ubiquitination of iRhom2 to enhance TACE maturation upon TNF\\u03b1 stimulation.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, and overexpression-based TACE maturation assays\",\n      \"pmids\": [\"29069608\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Largely overexpression-based without in vivo confirmation\", \"Ubiquitination site not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Generalized the antiviral role to RNA viruses, showing iRhom2 stabilizes VISA/MAVS by promoting degradation of the E3 ligases RNF5 and MARCH5.\",\n      \"evidence\": \"iRhom2-deficient cells, viral infection, ubiquitination, and VISA stability assays\",\n      \"pmids\": [\"29155878\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of selective E3-ligase degradation not fully resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"evidence\": \"Endogenous protein analysis in ADAM17-/- cells and domain-swap/point mutants in Adam17-/- and iRhom1/2-/- cells with shedding assays\",\n      \"pmids\": [\"32060096\", \"32103528\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not yet provide an experimental structure\", \"Substrate-selection code not fully decoded\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified iRhom2 turnover and metabolic-disease roles, with TRIM31 driving proteasomal degradation of iRhom2 and hepatic iRhom2 binding MAP3K7 to promote NF-\\u03baB/JNK and insulin-signaling defects under high-fat diet.\",\n      \"evidence\": \"Co-IP, proteasomal degradation assays, and hepatocyte-specific/myeloid-specific KO and transgenic mice with bone marrow transplantation\",\n      \"pmids\": [\"35217669\", \"32592194\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"MAP3K7 binding role versus canonical ADAM17 function not fully separated\", \"Single lab per finding\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"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.\",\n      \"evidence\": \"Lung cancer cell lines, iRhom2 KO, phosphorylation/14-3-3 recruitment, and tumor xenografts\",\n      \"pmids\": [\"35971826\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define which ERK-dependent residues are KRAS-specific\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined lipid-based regulation of iRhom2, with ZDHHC3 palmitoylating C476 to promote membrane translocation and block TRIM31-mediated degradation.\",\n      \"evidence\": \"S-palmitoylation assays, C476 mutagenesis, Co-IP, and ZDHHC3 KO hepatocytes with in vivo models\",\n      \"pmids\": [\"37544908\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not establish how palmitoylation intersects with the activation switch\", \"Single lab\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"evidence\": \"iRhom2 knockdown, ADAM17 surface and sIL-6R release assays, and ERK inhibition in mammary epithelial cells\",\n      \"pmids\": [\"37271223\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define the transcription factor mediating EGFR-driven induction\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Provided the first experimental structures of the ADAM17/iRhom2 complex, revealing trafficking, prodomain-retention inhibition, and prodomain-loss activation as three distinct regulatory mechanisms.\",\n      \"evidence\": \"Cryo-EM of inactive and active states with functional validation\",\n      \"pmids\": [\"38781971\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve cytoplasmic activation elements at high resolution\", \"Dynamics of prodomain release not directly observed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"evidence\": \"Biochemical cleavage assays, nuclear fractionation, CtBP Co-IP, RNA-seq, and patient skin biopsies\",\n      \"pmids\": [\"38183983\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the nuclear fragment's direct DNA/chromatin targets\", \"Relationship to membrane-bound iRhom2 pool unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"evidence\": \"14-3-3 binding and ADAM17 activity assays with TOC and cub allele mutagenesis and patient-cell comparison\",\n      \"pmids\": [\"38409522\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not structurally resolve the non-canonical 14-3-3 site\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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 \\u03b2).\",\n      \"evidence\": \"High-resolution proteomics and functional immune/phagocytosis assays in iRhom2-deficient macrophages and microglia\",\n      \"pmids\": [\"38570362\", \"40081988\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not establish in vivo consequences in neurodegeneration or anti-tumor immunity\", \"Single lab per finding\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"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.\",\n      \"evidence\": \"Cryo-EM of the ADAM17 zymogen/iRhom2 complex with cellular functional validation\",\n      \"pmids\": [\"40512800\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not capture the fully activated, substrate-engaged state dynamics\", \"Cytoplasmic switch elements only partly resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"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.\",\n      \"evidence\": \"Proteomic, genetic, and biochemical approaches with kinase-recruitment, FRMD8 overexpression, and RKR mutagenesis ADAM17 activity assays\",\n      \"pmids\": [\"40885391\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not define how the three mechanisms are temporally coordinated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP, microglia-specific RHBDF2 knockdown in MCAO/R mice, MeRIP, and RNA-seq\",\n      \"pmids\": [\"40898058\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not separate STING-pathway effects from ADAM17-dependent functions\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 4, 5, 11, 22, 27]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 9, 15, 22]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [22, 26]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 9]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 11, 17, 21]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [23]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 2, 4, 9, 15, 28]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 5, 22, 26]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 6, 11, 20, 31]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 9]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 6, 18, 29]}\n    ],\n    \"complexes\": [\"iRhom2-ADAM17 sheddase complex\"],\n    \"partners\": [\"ADAM17\", \"STING1\", \"MAVS\", \"FRMD8\", \"TRIM31\", \"ZDHHC3\", \"MAP3K7\", \"CTBP\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}