Glomulin (GLMN; also known as FAP48/FAP68, FKBP-associated protein) is a ~68 kDa, predominantly alpha-helical cytoplasmic protein (with a HEAT-repeat-like architecture) that functions as a regulatory component of cullin-RING ubiquitin ligase (CRL/SCF) complexes. It binds directly to the RING domain of RBX1 (ROC1) through its C-terminal half and masks the surface that RBX1 uses to recruit the E2 ubiquitin-conjugating enzyme CDC34, thereby inhibiting RBX1-dependent E3 ubiquitin ligase activity and blocking RBX1-mediated neddylation of CUL1. By sequestering RBX1, glomulin stabilizes assembled SCF/CRL components and controls the auto-ubiquitination and turnover of the F-box substrate receptor FBXW7, thereby influencing the abundance of FBXW7 substrates such as Cyclin E and c-Myc. Glomulin has been found in CRL/SCF assemblies containing RBX1 with CUL1, CUL2, CUL3, CUL4A, and in a CUL7-RBX1-SKP1-FBXW8 complex. Loss-of-function mutations in GLMN cause glomuvenous malformations, cutaneous venous lesions with abnormal smooth-muscle-like glomus cells, reflecting a requirement for glomulin in normal vascular development. An alternatively spliced shorter isoform (isoform 2, FAP48) was originally characterized as a ligand of the immunophilins FKBP12 (FKBP1A) and FKBP52 (FKBP4), and glomulin/FAP68 was also reported to bind the inactive hepatocyte growth factor receptor (MET) and modulate downstream p70 S6 kinase signaling; these immunophilin- and receptor-associated activities predate the discovery of the CRL-regulatory role and are mechanistically distinct from it. In innate immunity, glomulin also binds the RING domains of the cellular inhibitor of apoptosis proteins cIAP1 and cIAP2, inhibits their self-ubiquitination, and acts as a negative regulator of cIAP-mediated inflammasome activation and macrophage pyroptosis; the Shigella effector IpaH7.8 ubiquitinates glomulin to drive its degradation and enhance inflammation. Structurally, glomulin binds RBX1 with high affinity (Kd in the nanomolar range) through a region in its C-terminal half (approximately residues 300-594) that occludes the RBX1 surface used to recruit the E2 enzyme CDC34.
Definition: Any process that decreases the rate, frequency, or extent of inflammasome activation that is dependent on cellular inhibitor of apoptosis proteins (cIAP1/BIRC2, cIAP2/BIRC3), for example by a regulatory protein binding the cIAP RING domain and inhibiting cIAP self-ubiquitination.
Justification: Glomulin binds the RING domains of cIAP1 and cIAP2, inhibits their self-ubiquitination, and acts as a negative regulator of cIAP-mediated inflammasome activation and macrophage pyroptosis (Suzuki et al. 2018 EMBO Reports; the Shigella effector IpaH7.8 degrades glomulin to enhance inflammation). This innate-immunity function is mechanistically distinct from the CRL/SCF-regulatory role and is not captured by any existing GLMN GO annotation, representing a genuine gap. No sufficiently specific existing GO term was identified, so this is proposed without an invented GO ID.
Supporting Evidence:
Definition: Binding to the RING domain of a RING-type ubiquitin-protein ligase and inhibiting its E3 ligase activity, for example by masking the surface used to recruit a ubiquitin-conjugating (E2) enzyme, thereby blocking ubiquitin transfer.
Justification: Glomulin's defining biochemical activity is direct binding to RING-domain E3 components (RBX1, and also cIAP1/cIAP2) with masking of the E2-binding surface. The existing GO:0055105 ubiquitin-protein transferase inhibitor activity captures the inhibition but a RING-specific, E2-masking inhibitor term would more precisely describe the structurally characterized mechanism (Duda et al. 2012). Proposed without an invented GO ID; may already be partially covered, listed for curator consideration.
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0055105 ubiquitin-protein transferase inhibitor activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic assignment of the core glomulin molecular function, inhibition of ubiquitin-protein transferase (E3 ligase) activity via RBX1 binding. Reason: This is the experimentally established core molecular function of glomulin; it binds the RBX1 RING domain with high affinity (Kd ~38.6 nM, via a minimal region around residues 300-594) and masks the E2-binding surface, outcompeting the E2 CDC34 to inhibit ubiquitin chain synthesis by neddylated CUL1-RBX1/SCF complexes. This is a non-catalytic, inhibitory regulatory activity, not a ligase activity, consistent with the gene's biological role as a CRL assembly/activity regulator rather than an E3 ligase. Supporting Evidence: file:human/GLMN/GLMN-uniprot.txt Inhibits E3 ubiquitin ligase activity by binding to RBX1 (via RING domain) and inhibiting its interaction with the E2 ubiquitin-conjugating enzyme CDC34 file:human/GLMN/GLMN-deep-research-falcon.md GLMN **masks the E2-binding site** on RBX1, thereby **outcompeting** the E2 enzyme **CDC34** and **inhibiting ubiquitin chain synthesis** by neddylated CUL1–RBX1 and SCF complexes. |
| GO:0005515 protein binding | IPI PMID:25036637 A quantitative chaperone interaction network reveals the arc... | KEEP AS NON CORE | Summary: Interaction with FKBP4 (FKBP52) captured in a quantitative chaperone interaction network. Bare protein binding is uninformative. Reason: Records a real FKBP4 interaction but the bare protein binding term is uninformative per curation guidelines; the immunophilin association is a secondary, non-core property. Supporting Evidence: file:human/GLMN/GLMN-uniprot.txt Interacts with FKBP4 and FKBP1A |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: High-throughput binary interactome capturing multiple glomulin partners (EFS, RBX1, FKBP4, PEX5, SNAI1). Bare protein binding is uninformative. Reason: Real IntAct interactions (including the functionally important RBX1 partner) but bare protein binding is uninformative and not a core function statement. Supporting Evidence: file:human/GLMN/GLMN-uniprot.txt Q92990; P62877: RBX1; NbExp=7; IntAct=EBI-726150, EBI-398523 |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: Cell-specific proteome-scale interactome capturing glomulin partners including RBX1 and FKBP4. Bare protein binding is uninformative. Reason: High-throughput interactome; bare protein binding is uninformative and not a core function. Supporting Evidence: file:human/GLMN/GLMN-uniprot.txt Q92990; P62877: RBX1; NbExp=7; IntAct=EBI-726150, EBI-398523 |
| GO:0032743 positive regulation of interleukin-2 production | IDA PMID:12604780 The FKBP-associated protein FAP48 is an antiproliferative mo... | KEEP AS NON CORE | Summary: FAP48 (isoform 2)-FKBP complexes were reported to increase IL-2 production in a Jurkat T-cell overexpression model. A secondary, isoform-associated immunological role. Reason: Supported by the overexpression study but represents an older, isoform-2 (FAP48)/immunophilin-associated activity distinct from the core CRL-regulatory function; an overexpression phenotype rather than a direct molecular role. Supporting Evidence: PMID:12604780 contrary to FK506, which blocks IL2 synthesis, we observed that FAP48-FKBP complexes increase IL2 production |
| GO:0005102 signaling receptor binding | IDA PMID:8955134 FAP48, a new protein that forms specific complexes with both... | UNDECIDED | Summary: This reference characterizes FAP48 binding to the immunophilins FKBP59/FKBP12, not to a signaling receptor; the signaling receptor binding term is not supported by this paper. Reason: The cited paper (PMID:8955134) documents FAP48 binding to FKBP59/FKBP12 (immunophilins, peptidyl-prolyl isomerases), not a signaling receptor. The MGC/MGI annotation to GO:0005102 appears mismatched to this reference; the better-supported receptor interaction (MET) is captured separately under GO:0005171. Cannot confirm signaling receptor binding from the available abstract, so deferring rather than removing an experimental annotation. Supporting Evidence: PMID:8955134 a 48-kDa protein that specifically interacts with the peptidyl prolyl isomerase FK506-binding protein 59 (FKBP59) and also with the well known FKBP12 |
| GO:0005171 hepatocyte growth factor receptor binding | IDA PMID:11571281 Ligand-regulated binding of FAP68 to the hepatocyte growth f... | KEEP AS NON CORE | Summary: Glomulin/FAP68 binds the intracellular tail of the inactive hepatocyte growth factor receptor (MET) and is released upon MET phosphorylation. A real but secondary interaction. Reason: Directly demonstrated MET binding via yeast two-hybrid and co-immunoprecipitation, but this receptor association is a secondary role distinct from the core CRL/RBX1-regulatory function. Supporting Evidence: PMID:11571281 FAP68 interacts specifically with the inactive form of HGF receptor, such as a kinase-defective receptor or a dephosphorylated wild type receptor |
| GO:0007166 cell surface receptor signaling pathway | IDA PMID:12604780 The FKBP-associated protein FAP48 is an antiproliferative mo... | KEEP AS NON CORE | Summary: Generic cell surface receptor signaling assignment from the T-cell activation/IL-2 study. Overly generic and tied to a secondary role. Reason: The supporting study concerns FAP48 effects on T-cell activation/proliferation; this very general process term reflects a secondary immunological role, not the core CRL-regulatory function. Supporting Evidence: PMID:12604780 a player in T cell activation that increases IL2 synthesis |
| GO:0008285 negative regulation of cell population proliferation | IDA PMID:12604780 The FKBP-associated protein FAP48 is an antiproliferative mo... | KEEP AS NON CORE | Summary: FAP48 overexpression inhibits proliferation of Jurkat T cells. A secondary, isoform-associated antiproliferative phenotype. Reason: Supported by the overexpression phenotype, but reflects a secondary FAP48/immunophilin-context role rather than the core CRL-regulatory molecular function. Mechanistically may relate to FBXW7/Cyclin E-c-Myc control, but is not directly demonstrated as such here. Supporting Evidence: PMID:12604780 overexpression of FAP48 results in the inhibition of cellular proliferation as does the exposure of Jurkat T cells to FK506 |
| GO:0031462 Cul2-RING ubiquitin ligase complex | IPI PMID:22405651 The glomuvenous malformation protein Glomulin binds Rbx1 and... | ACCEPT | Summary: Glomulin was identified in complexes containing RBX1 plus a cullin, including CUL2. Reflects glomulin association with CRL2 assemblies via RBX1. Reason: Supported by the demonstration that glomulin is found in complexes containing RBX1 plus one of the cullins (CUL1, CUL2, CUL3, CUL4A); part_of a Cul2-RING complex is consistent with its RBX1-bridged CRL association. Supporting Evidence: file:human/GLMN/GLMN-uniprot.txt Identified in complexes that contain RBX1 plus one of the cullins CUL1, CUL2, CUL3, and CUL4A |
| GO:0031463 Cul3-RING ubiquitin ligase complex | IPI PMID:22405651 The glomuvenous malformation protein Glomulin binds Rbx1 and... | ACCEPT | Summary: Glomulin association with a CUL3-RBX1 CRL complex. Reason: Supported by identification of glomulin in RBX1-plus-cullin complexes including CUL3. Supporting Evidence: file:human/GLMN/GLMN-uniprot.txt Identified in complexes that contain RBX1 plus one of the cullins CUL1, CUL2, CUL3, and CUL4A |
| GO:0031464 Cul4A-RING E3 ubiquitin ligase complex | IPI PMID:22405651 The glomuvenous malformation protein Glomulin binds Rbx1 and... | ACCEPT | Summary: Glomulin association with a CUL4A-RBX1 CRL complex. Reason: Supported by identification of glomulin in RBX1-plus-cullin complexes including CUL4A. Supporting Evidence: file:human/GLMN/GLMN-uniprot.txt Identified in complexes that contain RBX1 plus one of the cullins CUL1, CUL2, CUL3, and CUL4A |
| GO:0031461 cullin-RING ubiquitin ligase complex | IPI PMID:22405651 The glomuvenous malformation protein Glomulin binds Rbx1 and... | ACCEPT | Summary: General cullin-RING ligase complex membership via RBX1 binding; the parent term covering glomulin's CRL associations. Reason: Correct general complex membership; glomulin is a regulatory component of cullin-RING/SCF complexes through RBX1. This is the appropriate in_complex term for the core function. Supporting Evidence: file:human/GLMN/GLMN-uniprot.txt Regulatory component of cullin-RING-based SCF (SKP1-Cullin-F-box protein) E3 ubiquitin-protein ligase complexes |
| GO:0031625 ubiquitin protein ligase binding | IDA PMID:22405651 The glomuvenous malformation protein Glomulin binds Rbx1 and... | ACCEPT | Summary: Glomulin binds directly to the RING-domain E3 ligase component RBX1. Captures the key binding event underlying its inhibitory function. Reason: Directly demonstrated binding to RBX1 (the RING E3 component); this binding underlies the core inhibitory molecular function and is more informative than bare protein binding. Supporting Evidence: PMID:22405651 Glomulin (Glmn), a protein found mutated in the vascular disorder glomuvenous malformation (GVM), binds directly to the RING domain of Rbx1 and inhibits its E3 ubiquitin ligase activity |
| GO:0032434 regulation of proteasomal ubiquitin-dependent protein catabolic process | IMP PMID:22405651 The glomuvenous malformation protein Glomulin binds Rbx1 and... | ACCEPT | Summary: Glomulin loss alters CRL/proteasome-dependent turnover of FBXW7 (and consequently Cyclin E and c-Myc). Captures the downstream biological process glomulin regulates. Reason: Supported by mutant-phenotype evidence that glomulin loss increases CRL/proteasome-dependent FBXW7 turnover; this is the core biological process glomulin regulates via CRL inhibition. Supporting Evidence: PMID:22405651 The increased turnover of Fbw7 is dependent on CRL and proteasome activity, indicating that Glmn modulates the E3 activity of CRL1(Fbw7) |
| GO:0055105 ubiquitin-protein transferase inhibitor activity | IGI PMID:22405651 The glomuvenous malformation protein Glomulin binds Rbx1 and... | ACCEPT | Summary: Genetic-interaction (with RBX1) evidence for the core inhibitory molecular function of glomulin on E3 ligase activity. Reason: Core molecular function with direct experimental support; glomulin binding to RBX1 inhibits its E3 ubiquitin ligase activity and CDC34 recruitment. Supporting Evidence: PMID:22405651 binds directly to the RING domain of Rbx1 and inhibits its E3 ubiquitin ligase activity |
| GO:0005515 protein binding | IPI PMID:11164950 Mutation of FKBP associated protein 48 (FAP48) at proline 21... | KEEP AS NON CORE | Summary: Interaction with FKBP4 (FKBP52) and FKBP1A (FKBP12); a Pro219 mutation disrupts the interaction. Bare protein binding is uninformative. Reason: Records the real immunophilin (FKBP) interaction but bare protein binding is uninformative; the FKBP association is a secondary, non-core property. Supporting Evidence: file:human/GLMN/GLMN-uniprot.txt P->A: Loss of interaction with FKBP4 and FKBP1A. |
| GO:0005515 protein binding | IPI PMID:12604780 The FKBP-associated protein FAP48 is an antiproliferative mo... | KEEP AS NON CORE | Summary: Interaction with FKBP4 captured in the FAP48 T-cell study. Bare protein binding is uninformative. Reason: Real FKBP4 interaction but bare protein binding is uninformative and not a core function. Supporting Evidence: file:human/GLMN/GLMN-uniprot.txt Interacts with FKBP4 and FKBP1A |
| GO:0001570 vasculogenesis | IMP PMID:11845407 Mutations in a novel factor, glomulin, are responsible for g... | KEEP AS NON CORE | Summary: Loss-of-function GLMN mutations cause glomuvenous malformations with abnormal vascular smooth-muscle cells, implicating glomulin in normal vascular development. A genuine but downstream/physiological role. Reason: Strongly supported by human genetics (loss-of-function mutations cause GVM); reflects an organismal/developmental consequence of the molecular CRL-regulatory function rather than the core molecular activity itself. UniProt notes essential role in vasculature development. Supporting Evidence: PMID:11845407 glomulin plays an important role in differentiation of these cells--and, thereby, in vascular morphogenesis--especially in cutaneous veins |
| GO:0001819 positive regulation of cytokine production | IMP PMID:12604780 The FKBP-associated protein FAP48 is an antiproliferative mo... | KEEP AS NON CORE | Summary: Generic parent of the IL-2 production phenotype seen on FAP48 overexpression. Secondary, isoform-associated immunological role. Reason: Supported as a generic parent of the IL-2 result from the FAP48 overexpression study; a secondary role, and more general than the specific IL-2 annotation. Supporting Evidence: PMID:12604780 FAP48-FKBP complexes increase IL2 production |
| GO:0032743 positive regulation of interleukin-2 production | IMP PMID:12604780 The FKBP-associated protein FAP48 is an antiproliferative mo... | KEEP AS NON CORE | Summary: FAP48 overexpression increases IL-2 production in Jurkat T cells. Secondary, isoform-associated immunological role (duplicate aspect of the IDA annotation above). Reason: Supported by the overexpression phenotype but a secondary FAP48/immunophilin-context role distinct from the core CRL-regulatory function. Supporting Evidence: PMID:12604780 FAP48-FKBP complexes increase IL2 production |
| GO:0040029 epigenetic regulation of gene expression | IMP PMID:12604780 The FKBP-associated protein FAP48 is an antiproliferative mo... | UNDECIDED | Summary: The cited FAP48 T-cell study reports altered expression of argininosuccinate synthetase and Mxi1 on FAP48 overexpression but does not demonstrate an epigenetic mechanism; the term appears to over-interpret the data. Reason: The supporting paper shows changes in target protein levels (ASS, Mxi1) following FAP48 overexpression, but provides no evidence of an epigenetic (e.g., chromatin/DNA-methylation) mechanism. The mapping to GO:0040029 looks like an over-interpretation; deferring rather than removing an experimental annotation whose full text was not read. Supporting Evidence: PMID:12604780 the expression levels of argininosuccinate synthetase and the Myc antagonist Mxi1 are modified by overexpression of FAP48 |
| GO:0042130 negative regulation of T cell proliferation | IDA PMID:12604780 The FKBP-associated protein FAP48 is an antiproliferative mo... | KEEP AS NON CORE | Summary: FAP48 overexpression inhibits proliferation of Jurkat T cells, consistent with negative regulation of T-cell proliferation. Secondary, isoform-associated role. Reason: Supported by the overexpression phenotype in T cells but a secondary FAP48-context role rather than the core CRL-regulatory function. Supporting Evidence: PMID:12604780 overexpression of FAP48 results in the inhibition of cellular proliferation as does the exposure of Jurkat T cells to FK506 |
| GO:0042692 muscle cell differentiation | IMP PMID:11845407 Mutations in a novel factor, glomulin, are responsible for g... | KEEP AS NON CORE | Summary: GVM lesions show abnormal smooth-muscle-like glomus cells, suggesting glomulin contributes to (vascular smooth) muscle cell differentiation. A downstream developmental role. Reason: Supported by the GVM phenotype (abnormal vascular smooth-muscle-like cells) but a downstream developmental consequence of the molecular function, not the core activity. Supporting Evidence: PMID:11845407 glomulin plays an important role in differentiation of these cells--and, thereby, in vascular morphogenesis |
| GO:0005171 hepatocyte growth factor receptor binding | IPI PMID:11571281 Ligand-regulated binding of FAP68 to the hepatocyte growth f... | KEEP AS NON CORE | Summary: IPI evidence (with MET, UniProtKB:P08581) for glomulin/FAP68 binding the hepatocyte growth factor receptor. Duplicate aspect of the IDA annotation above; a secondary interaction. Reason: Directly supported MET interaction but a secondary role distinct from the core CRL/RBX1-regulatory function. Supporting Evidence: PMID:11571281 FAP68 interacts specifically with the inactive form of HGF receptor, such as a kinase-defective receptor or a dephosphorylated wild type receptor |
| GO:0042327 positive regulation of phosphorylation | IDA PMID:11571281 Ligand-regulated binding of FAP68 to the hepatocyte growth f... | KEEP AS NON CORE | Summary: Free FAP68 stimulates the downstream kinase p70 S6 kinase (RPS6KB1), increasing its activity/phosphorylation. A secondary signaling role. Reason: Supported by the demonstration that free FAP68 stimulates p70S6K downstream of MET; a secondary signaling role distinct from the core CRL-regulatory function. UniProt notes contribution to RPS6KB1 phosphorylation. Supporting Evidence: PMID:11571281 Free FAP68 exerts a specific stimulatory activity toward the downstream target p70 S6 protein kinase (p70S6K) |
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Download this section (compressed HTML)Q: How is glomulin's inhibition of RBX1/CRL activity relieved in cells (e.g., by neddylation status, CAND1-type exchange, or competing F-box receptors), and what signals trigger glomulin release from assembled CRLs?
Q: To what extent are glomulin's secondary roles (FKBP/immunophilin binding, MET receptor binding and p70S6K stimulation, T-cell IL-2 effects) mechanistically connected to its core CRL-regulatory function versus independent moonlighting activities?
Q: Does glomulin use the same RBX1-binding region (residues ~300-594, masking the E2/CDC34-binding surface) to engage the RING domains of cIAP1/cIAP2, and is the cIAP-inflammasome regulatory function genetically separable from the CRL-regulatory function in glomuvenous malformation versus innate-immune contexts?
Experiment: Reconstitute SCF(FBXW7) ubiquitination in vitro with purified glomulin, RBX1, CUL1, SKP1, FBXW7, CDC34/UBE2R and NEDD8 machinery to quantify how glomulin inhibits CDC34 recruitment, neddylation, and FBXW7 auto-ubiquitination, including with GVM-associated and RBX1-binding-deficient (K425A/N476A/L567A/R574A) glomulin variants.
Experiment: Perform quantitative proteomics and CRL substrate-stability assays in GLMN-null versus wild-type cells (and in patient-derived GVM tissue) to define the cullin-RING ligase substrate repertoire stabilized or destabilized by glomulin loss across CUL1/2/3/4A complexes.
Experiment: In macrophages, test whether RBX1-binding-deficient glomulin variants retain cIAP1/cIAP2 binding and inhibition of cIAP self-ubiquitination, and measure inflammasome activation/caspase-1 puncta and pyroptosis upon GLMN depletion or Shigella IpaH7.8 expression, to map whether one binding surface mediates both CRL and cIAP regulation.
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