RHBDF1

# yaml-language-server: $schema=../../../src/ai_gene_review/schema/gene_review.yaml
id: Q96CC6
gene_symbol: RHBDF1
product_type: PROTEIN
status: DRAFT
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 'RHBDF1 (iRhom1; inactive rhomboid protein 1) is an endoplasmic-reticulum / Golgi membrane
  protein of the rhomboid peptidase S54 family. Unlike active rhomboid intramembrane serine proteases,
  iRhom1 is a catalytically dead pseudoprotease: it lacks the catalytic serine and has no serine-type
  endopeptidase activity. Instead it functions as a regulatory scaffold for the metalloprotease ADAM17/TACE,
  controlling ADAM17 maturation, ER-to-Golgi trafficking, stability and substrate selectivity (together
  with partners such as FRMD8/iTAP), and thereby governing the shedding of EGFR ligands and TNF, i.e.
  regulation of EGFR signaling and regulated protein secretion. Acting through the ER quality-control
  machinery, it also influences ER-associated degradation and, under ER stress, proteasome assembly via
  PAC1/2. It is widely expressed (notably cerebellum, cerebrum, heart) and its dysregulation promotes
  proliferation and migration in epithelial cancers.'
existing_annotations:
- term:
    id: GO:0004252
    label: serine-type endopeptidase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  negated: true
  review:
    summary: 'NOT (negated): RHBDF1 (iRhom1) does NOT have serine-type endopeptidase activity. Although
      it belongs to the rhomboid peptidase S54 family, it is an inactive rhomboid (pseudoprotease) lacking
      the catalytic Ser (position 720).'
    action: ACCEPT
    reason: Correct and important negation. iRhom1 is a catalytically dead rhomboid; the curated NOT faithfully
      encodes the loss of protease activity flagged by the UniProt CAUTION. Retain.
    supported_by: &id005
    - reference_id: file:human/RHBDF1/RHBDF1-uniprot.txt
      supporting_text: Lacks serine protease activity as it lacks the catalytic Ser
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: ER membrane localization, the principal residence of iRhom1.
    action: ACCEPT
    reason: Well supported by multiple EXP/IDA lines and UniProt; core localization.
    supported_by: &id001
    - reference_id: file:human/RHBDF1/RHBDF1-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
- term:
    id: GO:0042058
    label: regulation of epidermal growth factor receptor signaling pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Regulation of EGFR signaling pathway. iRhom1 controls maturation/trafficking of ADAM17, the
      sheddase that releases EGFR ligands, thereby regulating EGFR signaling.
    action: ACCEPT
    reason: Core biological process, supported experimentally (IMP) and by phylogenetic inference. Central
      to iRhom1 function.
    supported_by: &id003
    - reference_id: file:human/RHBDF1/RHBDF1-uniprot.txt
      supporting_text: Regulates ADAM17 protease, a sheddase of the epidermal growth
- term:
    id: GO:0050708
    label: regulation of protein secretion
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: 'Regulation of protein secretion: iRhom1 governs the maturation of ADAM17 and shedding/secretion
      of its substrates.'
    action: ACCEPT
    reason: Core process tied to the iRhom/ADAM17 sheddase axis; experimentally supported.
    supported_by: &id004
    - reference_id: file:human/RHBDF1/RHBDF1-uniprot.txt
      supporting_text: Regulates ADAM17 protease, a sheddase of the epidermal growth
- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Golgi membrane localization; iRhom1 traffics ADAM17 through the secretory pathway.
    action: ACCEPT
    reason: Supported by EXP/IDA evidence; consistent with its trafficking role.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  review:
    summary: Broad membrane/endomembrane/cytoplasm localization by IEA.
    action: KEEP_AS_NON_CORE
    reason: Correct but non-specific; the precise compartments (ER and Golgi membranes) are separately
      annotated.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: ER membrane localization, the principal residence of iRhom1.
    action: ACCEPT
    reason: Well supported by multiple EXP/IDA lines and UniProt; core localization.
    supported_by: *id001
- term:
    id: GO:0012505
    label: endomembrane system
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  review:
    summary: Broad membrane/endomembrane/cytoplasm localization by IEA.
    action: KEEP_AS_NON_CORE
    reason: Correct but non-specific; the precise compartments (ER and Golgi membranes) are separately
      annotated.
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Broad membrane/endomembrane/cytoplasm localization by IEA.
    action: KEEP_AS_NON_CORE
    reason: Correct but non-specific; the precise compartments (ER and Golgi membranes) are separately
      annotated.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: Generic 'protein binding' from a large-scale binary interactome screen; no specific functional
      signal.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput interactome protein binding; uninformative about molecular function. Over-annotation.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26109405
  qualifier: enables
  review:
    summary: IPI 'protein binding'; iRhom1 acts as a scaffold and interacts with functionally relevant
      partners (ADAM17/TACE, FRMD8/iTAP, PAC1/2). The interaction supports its adapter role but the generic
      term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real, functionally meaningful interaction underpinning the scaffold function, but 'protein
      binding' itself is uninformative (curation guideline); keep as non-core supporting evidence.
    supported_by: &id002
    - reference_id: file:human/RHBDF1/RHBDF1-uniprot.txt
      supporting_text: Belongs to the peptidase S54 family
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:26109405
  qualifier: located_in
  review:
    summary: ER localization (IDA).
    action: ACCEPT
    reason: Direct evidence; consistent with core ER residence.
- term:
    id: GO:0051131
    label: chaperone-mediated protein complex assembly
  evidence_type: IMP
  original_reference_id: PMID:26109405
  qualifier: involved_in
  review:
    summary: 'Chaperone-mediated protein complex assembly: iRhom1 regulates proteasome assembly via PAC1/2
      under ER stress (PMID:26109405).'
    action: KEEP_AS_NON_CORE
    reason: Experimentally supported but a specialized stress-context role, non-core relative to the iRhom/ADAM17
      axis.
    supported_by:
    - reference_id: PMID:26109405
      supporting_text: iRhom1 regulates proteasome activity via PAC1/2 under ER stress
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29897333
  qualifier: enables
  review:
    summary: IPI 'protein binding'; iRhom1 acts as a scaffold and interacts with functionally relevant
      partners (ADAM17/TACE, FRMD8/iTAP, PAC1/2). The interaction supports its adapter role but the generic
      term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real, functionally meaningful interaction underpinning the scaffold function, but 'protein
      binding' itself is uninformative (curation guideline); keep as non-core supporting evidence.
    supported_by: *id002
- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: EXP
  original_reference_id: PMID:15965977
  qualifier: located_in
  review:
    summary: Golgi membrane localization; iRhom1 traffics ADAM17 through the secretory pathway.
    action: ACCEPT
    reason: Supported by EXP/IDA evidence; consistent with its trafficking role.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:15965977
  qualifier: located_in
  review:
    summary: ER membrane localization, the principal residence of iRhom1.
    action: ACCEPT
    reason: Well supported by multiple EXP/IDA lines and UniProt; core localization.
    supported_by: *id001
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29897336
  qualifier: enables
  review:
    summary: IPI 'protein binding'; iRhom1 acts as a scaffold and interacts with functionally relevant
      partners (ADAM17/TACE, FRMD8/iTAP, PAC1/2). The interaction supports its adapter role but the generic
      term is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real, functionally meaningful interaction underpinning the scaffold function, but 'protein
      binding' itself is uninformative (curation guideline); keep as non-core supporting evidence.
    supported_by: *id002
- term:
    id: GO:0000139
    label: Golgi membrane
  evidence_type: IDA
  original_reference_id: PMID:18832597
  qualifier: located_in
  review:
    summary: Golgi membrane localization; iRhom1 traffics ADAM17 through the secretory pathway.
    action: ACCEPT
    reason: Supported by EXP/IDA evidence; consistent with its trafficking role.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:18832597
  qualifier: located_in
  review:
    summary: ER membrane localization, the principal residence of iRhom1.
    action: ACCEPT
    reason: Well supported by multiple EXP/IDA lines and UniProt; core localization.
    supported_by: *id001
- term:
    id: GO:0008283
    label: cell population proliferation
  evidence_type: IMP
  original_reference_id: PMID:18832597
  qualifier: involved_in
  review:
    summary: Cell population proliferation (IMP) in head-and-neck cancer cells via GPCR-EGFR transactivation.
    action: KEEP_AS_NON_CORE
    reason: Downstream physiological/disease phenotype, non-core relative to the molecular regulatory
      role.
- term:
    id: GO:0016477
    label: cell migration
  evidence_type: IMP
  original_reference_id: PMID:18832597
  qualifier: involved_in
  review:
    summary: Cell migration (IMP), a downstream phenotype of iRhom1/EGFR signaling in cancer cells.
    action: KEEP_AS_NON_CORE
    reason: Downstream physiological phenotype; non-core.
- term:
    id: GO:0042058
    label: regulation of epidermal growth factor receptor signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:18832597
  qualifier: involved_in
  review:
    summary: Regulation of EGFR signaling pathway. iRhom1 controls maturation/trafficking of ADAM17, the
      sheddase that releases EGFR ligands, thereby regulating EGFR signaling.
    action: ACCEPT
    reason: Core biological process, supported experimentally (IMP) and by phylogenetic inference. Central
      to iRhom1 function.
    supported_by: *id003
- term:
    id: GO:0050708
    label: regulation of protein secretion
  evidence_type: IMP
  original_reference_id: PMID:18832597
  qualifier: involved_in
  review:
    summary: 'Regulation of protein secretion: iRhom1 governs the maturation of ADAM17 and shedding/secretion
      of its substrates.'
    action: ACCEPT
    reason: Core process tied to the iRhom/ADAM17 sheddase axis; experimentally supported.
    supported_by: *id004
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:21439629
  qualifier: located_in
  review:
    summary: ER membrane localization, the principal residence of iRhom1.
    action: ACCEPT
    reason: Well supported by multiple EXP/IDA lines and UniProt; core localization.
    supported_by: *id001
- term:
    id: GO:0050709
    label: negative regulation of protein secretion
  evidence_type: IDA
  original_reference_id: PMID:21439629
  qualifier: involved_in
  review:
    summary: 'Negative regulation of protein secretion (IDA, PMID:21439629): rhomboid pseudoproteases
      use ER quality-control to retain/regulate secretion of client proteins.'
    action: ACCEPT
    reason: Experimentally supported core regulatory process for an inactive rhomboid.
    supported_by:
    - reference_id: PMID:21439629
      supporting_text: Rhomboid family pseudoproteases use the ER quality control machinery to regulate
        intercellular signaling
- term:
    id: GO:0061136
    label: regulation of proteasomal protein catabolic process
  evidence_type: IDA
  original_reference_id: PMID:21439629
  qualifier: involved_in
  review:
    summary: 'Regulation of proteasomal protein catabolic process (IDA): iRhom1 routes clients to ER-associated
      degradation / regulates proteasome activity.'
    action: KEEP_AS_NON_CORE
    reason: Experimentally supported but a non-core facet relative to the ADAM17/EGFR sheddase-regulation
      function.
    supported_by:
    - reference_id: PMID:21439629
      supporting_text: Rhomboid family pseudoproteases use the ER quality control machinery to regulate
        intercellular signaling
- term:
    id: GO:0004252
    label: serine-type endopeptidase activity
  evidence_type: IDA
  original_reference_id: PMID:21439629
  qualifier: enables
  negated: true
  review:
    summary: 'NOT (negated): RHBDF1 (iRhom1) does NOT have serine-type endopeptidase activity. Although
      it belongs to the rhomboid peptidase S54 family, it is an inactive rhomboid (pseudoprotease) lacking
      the catalytic Ser (position 720).'
    action: ACCEPT
    reason: Correct and important negation. iRhom1 is a catalytically dead rhomboid; the curated NOT faithfully
      encodes the loss of protease activity flagged by the UniProt CAUTION. Retain.
    supported_by: *id005
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: GO annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping
  findings: []
- id: GO_REF:0000117
  title: Automatic GO annotation from UniProtKB-KW mapping
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:15965977
  title: Characterization of a human rhomboid homolog, p100hRho/RHBDF1, which interacts with TGF-alpha
    family ligands.
  findings:
  - statement: iRhom1 interacts with TGF-alpha family ligands and is an ER/Golgi membrane rhomboid homolog.
    supporting_text: Characterization of a human rhomboid homolog, p100hRho/RHBDF1
  reference_review: &id006
    relevance: HIGH
    correctness: VERIFIED
- id: PMID:18832597
  title: Human rhomboid family-1 gene RHBDF1 participates in GPCR-mediated transactivation of EGFR growth
    signals in head and neck squamous cancer cells.
  findings:
  - statement: RHBDF1 participates in GPCR-mediated transactivation of EGFR growth signals in cancer cells.
    supporting_text: Human rhomboid family-1 gene RHBDF1 participates in GPCR-mediated transactivation
      of EGFR growth signals in head and neck squamous cancer cells
  reference_review: *id006
- id: PMID:21439629
  title: Rhomboid family pseudoproteases use the ER quality control machinery to regulate intercellular
    signaling.
  findings:
  - statement: Rhomboid pseudoproteases use ER quality control to regulate intercellular (EGF/ADAM17)
      signaling; iRhom1 has no protease activity.
    supporting_text: Rhomboid family pseudoproteases use the ER quality control machinery to regulate
      intercellular signaling
  reference_review: *id006
- id: PMID:26109405
  title: iRhom1 regulates proteasome activity via PAC1/2 under ER stress.
  findings:
  - statement: iRhom1 regulates proteasome activity via PAC1/2 under ER stress.
    supporting_text: iRhom1 regulates proteasome activity via PAC1/2 under ER stress
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
- id: PMID:29897333
  title: iTAP, a novel iRhom interactor, controls TNF secretion by policing the stability of iRhom/TACE.
  findings:
  - statement: iTAP/FRMD8 is an iRhom interactor controlling TNF secretion by stabilizing iRhom/TACE.
    supporting_text: iTAP, a novel iRhom interactor, controls TNF secretion by policing the stability
      of iRhom/TACE
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
- id: PMID:29897336
  title: FRMD8 promotes inflammatory and growth factor signalling by stabilising the iRhom/ADAM17 sheddase
    complex.
  findings:
  - statement: FRMD8 stabilizes the iRhom/ADAM17 sheddase complex to promote inflammatory and growth-factor
      signaling.
    supporting_text: FRMD8 promotes inflammatory and growth factor signalling by stabilising the iRhom/ADAM17
      sheddase complex
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; supports only generic protein binding.
- id: file:human/RHBDF1/RHBDF1-uniprot.txt
  title: UniProt entry Q96CC6 (RHBDF1)
  findings:
  - statement: iRhom1 lacks serine protease activity (no catalytic Ser-720).
    supporting_text: Lacks serine protease activity as it lacks the catalytic Ser
  - statement: Regulates ADAM17, a sheddase of EGF-receptor ligands.
    supporting_text: Regulates ADAM17 protease, a sheddase of the epidermal growth
aliases:
- iRhom1
- RHO
- DIST1
- C16orf8
- p100hRho
- Inactive rhomboid protein 1
core_functions:
- description: Catalytically inactive rhomboid (pseudoprotease) that acts as an ER/Golgi membrane scaffold
    regulating ADAM17/TACE maturation, trafficking and activity, thereby controlling shedding of EGFR
    ligands and TNF (regulation of EGFR signaling and protein secretion).
  directly_involved_in:
  - id: GO:0042058
    label: regulation of epidermal growth factor receptor signaling pathway
  - id: GO:0050708
    label: regulation of protein secretion
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  - id: GO:0000139
    label: Golgi membrane
  supported_by:
  - reference_id: PMID:21439629
    supporting_text: Rhomboid family pseudoproteases use the ER quality control machinery to regulate
      intercellular signaling
  - reference_id: file:human/RHBDF1/RHBDF1-uniprot.txt
    supporting_text: Regulates ADAM17 protease, a sheddase of the epidermal growth
suggested_questions:
- question: Do iRhom1 and iRhom2 (RHBDF2) have distinct ADAM17 substrate repertoires, or are they largely
    redundant in EGFR-ligand vs TNF shedding?
suggested_experiments:
- hypothesis: iRhom1 selectively controls shedding of a subset of ADAM17 substrates.
  description: Quantify shedding of a panel of ADAM17 substrates (EGF-family ligands, TNF) in RHBDF1-knockout
    vs RHBDF2-knockout cells with rescue constructs.