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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004252 serine-type endopeptidase activity | IBA NOT GO_REF:0000033 | ACCEPT | 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). 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. Supporting Evidence: file:human/RHBDF1/RHBDF1-uniprot.txt Lacks serine protease activity as it lacks the catalytic Ser |
| GO:0005789 endoplasmic reticulum membrane | IBA GO_REF:0000033 | ACCEPT | Summary: ER membrane localization, the principal residence of iRhom1. Reason: Well supported by multiple EXP/IDA lines and UniProt; core localization. Supporting Evidence: file:human/RHBDF1/RHBDF1-uniprot.txt Endoplasmic reticulum membrane |
| GO:0042058 regulation of epidermal growth factor receptor signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: Regulation of EGFR signaling pathway. iRhom1 controls maturation/trafficking of ADAM17, the sheddase that releases EGFR ligands, thereby regulating EGFR signaling. Reason: Core biological process, supported experimentally (IMP) and by phylogenetic inference. Central to iRhom1 function. Supporting Evidence: file:human/RHBDF1/RHBDF1-uniprot.txt Regulates ADAM17 protease, a sheddase of the epidermal growth |
| GO:0050708 regulation of protein secretion | IBA GO_REF:0000033 | ACCEPT | Summary: Regulation of protein secretion: iRhom1 governs the maturation of ADAM17 and shedding/secretion of its substrates. Reason: Core process tied to the iRhom/ADAM17 sheddase axis; experimentally supported. Supporting Evidence: file:human/RHBDF1/RHBDF1-uniprot.txt Regulates ADAM17 protease, a sheddase of the epidermal growth |
| GO:0000139 Golgi membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Golgi membrane localization; iRhom1 traffics ADAM17 through the secretory pathway. Reason: Supported by EXP/IDA evidence; consistent with its trafficking role. |
| GO:0005737 cytoplasm | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Broad membrane/endomembrane/cytoplasm localization by IEA. Reason: Correct but non-specific; the precise compartments (ER and Golgi membranes) are separately annotated. |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: ER membrane localization, the principal residence of iRhom1. Reason: Well supported by multiple EXP/IDA lines and UniProt; core localization. Supporting Evidence: file:human/RHBDF1/RHBDF1-uniprot.txt Endoplasmic reticulum membrane |
| GO:0012505 endomembrane system | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Broad membrane/endomembrane/cytoplasm localization by IEA. Reason: Correct but non-specific; the precise compartments (ER and Golgi membranes) are separately annotated. |
| GO:0016020 membrane | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Broad membrane/endomembrane/cytoplasm localization by IEA. Reason: Correct but non-specific; the precise compartments (ER and Golgi membranes) are separately annotated. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: Generic 'protein binding' from a large-scale binary interactome screen; no specific functional signal. Reason: High-throughput interactome protein binding; uninformative about molecular function. Over-annotation. |
| GO:0005515 protein binding | IPI PMID:26109405 iRhom1 regulates proteasome activity via PAC1/2 under ER str... | KEEP AS NON CORE | 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. Reason: Real, functionally meaningful interaction underpinning the scaffold function, but 'protein binding' itself is uninformative (curation guideline); keep as non-core supporting evidence. Supporting Evidence: file:human/RHBDF1/RHBDF1-uniprot.txt Belongs to the peptidase S54 family |
| GO:0005783 endoplasmic reticulum | IDA PMID:26109405 iRhom1 regulates proteasome activity via PAC1/2 under ER str... | ACCEPT | Summary: ER localization (IDA). Reason: Direct evidence; consistent with core ER residence. |
| GO:0051131 chaperone-mediated protein complex assembly | IMP PMID:26109405 iRhom1 regulates proteasome activity via PAC1/2 under ER str... | KEEP AS NON CORE | Summary: Chaperone-mediated protein complex assembly: iRhom1 regulates proteasome assembly via PAC1/2 under ER stress (PMID:26109405). Reason: Experimentally supported but a specialized stress-context role, non-core relative to the iRhom/ADAM17 axis. Supporting Evidence: PMID:26109405 iRhom1 regulates proteasome activity via PAC1/2 under ER stress |
| GO:0005515 protein binding | IPI PMID:29897333 iTAP, a novel iRhom interactor, controls TNF secretion by po... | KEEP AS NON CORE | 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. Reason: Real, functionally meaningful interaction underpinning the scaffold function, but 'protein binding' itself is uninformative (curation guideline); keep as non-core supporting evidence. Supporting Evidence: file:human/RHBDF1/RHBDF1-uniprot.txt Belongs to the peptidase S54 family |
| GO:0000139 Golgi membrane | EXP PMID:15965977 Characterization of a human rhomboid homolog, p100hRho/RHBDF... | ACCEPT | Summary: Golgi membrane localization; iRhom1 traffics ADAM17 through the secretory pathway. Reason: Supported by EXP/IDA evidence; consistent with its trafficking role. |
| GO:0005789 endoplasmic reticulum membrane | EXP PMID:15965977 Characterization of a human rhomboid homolog, p100hRho/RHBDF... | ACCEPT | Summary: ER membrane localization, the principal residence of iRhom1. Reason: Well supported by multiple EXP/IDA lines and UniProt; core localization. Supporting Evidence: file:human/RHBDF1/RHBDF1-uniprot.txt Endoplasmic reticulum membrane |
| GO:0005515 protein binding | IPI PMID:29897336 FRMD8 promotes inflammatory and growth factor signalling by ... | KEEP AS NON CORE | 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. Reason: Real, functionally meaningful interaction underpinning the scaffold function, but 'protein binding' itself is uninformative (curation guideline); keep as non-core supporting evidence. Supporting Evidence: file:human/RHBDF1/RHBDF1-uniprot.txt Belongs to the peptidase S54 family |
| GO:0000139 Golgi membrane | IDA PMID:18832597 Human rhomboid family-1 gene RHBDF1 participates in GPCR-med... | ACCEPT | Summary: Golgi membrane localization; iRhom1 traffics ADAM17 through the secretory pathway. Reason: Supported by EXP/IDA evidence; consistent with its trafficking role. |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:18832597 Human rhomboid family-1 gene RHBDF1 participates in GPCR-med... | ACCEPT | Summary: ER membrane localization, the principal residence of iRhom1. Reason: Well supported by multiple EXP/IDA lines and UniProt; core localization. Supporting Evidence: file:human/RHBDF1/RHBDF1-uniprot.txt Endoplasmic reticulum membrane |
| GO:0008283 cell population proliferation | IMP PMID:18832597 Human rhomboid family-1 gene RHBDF1 participates in GPCR-med... | KEEP AS NON CORE | Summary: Cell population proliferation (IMP) in head-and-neck cancer cells via GPCR-EGFR transactivation. Reason: Downstream physiological/disease phenotype, non-core relative to the molecular regulatory role. |
| GO:0016477 cell migration | IMP PMID:18832597 Human rhomboid family-1 gene RHBDF1 participates in GPCR-med... | KEEP AS NON CORE | Summary: Cell migration (IMP), a downstream phenotype of iRhom1/EGFR signaling in cancer cells. Reason: Downstream physiological phenotype; non-core. |
| GO:0042058 regulation of epidermal growth factor receptor signaling pathway | IMP PMID:18832597 Human rhomboid family-1 gene RHBDF1 participates in GPCR-med... | ACCEPT | Summary: Regulation of EGFR signaling pathway. iRhom1 controls maturation/trafficking of ADAM17, the sheddase that releases EGFR ligands, thereby regulating EGFR signaling. Reason: Core biological process, supported experimentally (IMP) and by phylogenetic inference. Central to iRhom1 function. Supporting Evidence: file:human/RHBDF1/RHBDF1-uniprot.txt Regulates ADAM17 protease, a sheddase of the epidermal growth |
| GO:0050708 regulation of protein secretion | IMP PMID:18832597 Human rhomboid family-1 gene RHBDF1 participates in GPCR-med... | ACCEPT | Summary: Regulation of protein secretion: iRhom1 governs the maturation of ADAM17 and shedding/secretion of its substrates. Reason: Core process tied to the iRhom/ADAM17 sheddase axis; experimentally supported. Supporting Evidence: file:human/RHBDF1/RHBDF1-uniprot.txt Regulates ADAM17 protease, a sheddase of the epidermal growth |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:21439629 Rhomboid family pseudoproteases use the ER quality control m... | ACCEPT | Summary: ER membrane localization, the principal residence of iRhom1. Reason: Well supported by multiple EXP/IDA lines and UniProt; core localization. Supporting Evidence: file:human/RHBDF1/RHBDF1-uniprot.txt Endoplasmic reticulum membrane |
| GO:0050709 negative regulation of protein secretion | IDA PMID:21439629 Rhomboid family pseudoproteases use the ER quality control m... | ACCEPT | Summary: Negative regulation of protein secretion (IDA, PMID:21439629): rhomboid pseudoproteases use ER quality-control to retain/regulate secretion of client proteins. Reason: Experimentally supported core regulatory process for an inactive rhomboid. Supporting Evidence: PMID:21439629 Rhomboid family pseudoproteases use the ER quality control machinery to regulate intercellular signaling |
| GO:0061136 regulation of proteasomal protein catabolic process | IDA PMID:21439629 Rhomboid family pseudoproteases use the ER quality control m... | KEEP AS NON CORE | Summary: Regulation of proteasomal protein catabolic process (IDA): iRhom1 routes clients to ER-associated degradation / regulates proteasome activity. Reason: Experimentally supported but a non-core facet relative to the ADAM17/EGFR sheddase-regulation function. Supporting Evidence: PMID:21439629 Rhomboid family pseudoproteases use the ER quality control machinery to regulate intercellular signaling |
| GO:0004252 serine-type endopeptidase activity | IDA NOT PMID:21439629 Rhomboid family pseudoproteases use the ER quality control m... | ACCEPT | 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). 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. Supporting Evidence: file:human/RHBDF1/RHBDF1-uniprot.txt Lacks serine protease activity as it lacks the catalytic Ser |
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Download this section (compressed HTML)Q: Do iRhom1 and iRhom2 (RHBDF2) have distinct ADAM17 substrate repertoires, or are they largely redundant in EGFR-ligand vs TNF shedding?
Experiment: Quantify shedding of a panel of ADAM17 substrates (EGF-family ligands, TNF) in RHBDF1-knockout vs RHBDF2-knockout cells with rescue constructs.
Hypothesis: iRhom1 selectively controls shedding of a subset of ADAM17 substrates.
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