MIB1 (Mind bomb 1) is a large multi-domain RING-type E3 ubiquitin-protein ligase (EC 2.3.2.27). Its N-terminal substrate-recognition region (MZM domain, flanked by two Mib-Herc2 modules, and the REP ankyrin/repeat region) engages two separate epitopes in the cytoplasmic tails of Notch ligands (the membrane-proximal N-box and a C-terminal C-box of JAG1 and Delta-like ligands), and its C-terminal RING domains recruit the E2 to transfer ubiquitin onto ligand lysines. Ligand ubiquitination by MIB1 triggers epsin-dependent endocytosis in the signal-sending cell, which generates the mechanical force required for Notch S2 cleavage and activation; MIB1 is the dominant ligand E3 ligase in mammals and is required for essentially all ligand-dependent Notch signaling during development. MIB1 also localizes to centriolar satellites, where it ubiquitinates PCM1, CEP131, CEP290 and GABARAP (restraining ciliogenesis and GABARAP-dependent autophagy), and it mediates K63-linked ubiquitination of TBK1 in antiviral RNA sensing and ubiquitination-dependent degradation of SMN.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004842 ubiquitin-protein transferase activity | IEA GO_REF:0000002 | ACCEPT | Summary: Ubiquitin-protein transferase activity (InterPro/Reactome). Reason: Correct parent of ubiquitin protein ligase activity; Reactome depicts MIB1 ubiquitinating DLL/JAG ligands. Supporting Evidence: file:human/MIB1/MIB1-uniprot.txt Positively regulates the Delta-mediated Notch signaling by ubiquitinating the intracellular domain of Delta, leading to endocytosis of Delta receptors. PMID:25747658 Individual mutation of either the N- or C-box epitope also attenuated the extent of ubiquitination, suggesting that the two binding sites cooperate to achieve efficient ubiquitin transfer. |
| GO:0004842 ubiquitin-protein transferase activity | TAS Reactome:R-HSA-2737728 | ACCEPT | Summary: Ubiquitin-protein transferase activity (InterPro/Reactome). Reason: Correct parent of ubiquitin protein ligase activity; Reactome depicts MIB1 ubiquitinating DLL/JAG ligands. Supporting Evidence: file:human/MIB1/MIB1-uniprot.txt Positively regulates the Delta-mediated Notch signaling by ubiquitinating the intracellular domain of Delta, leading to endocytosis of Delta receptors. PMID:25747658 Individual mutation of either the N- or C-box epitope also attenuated the extent of ubiquitination, suggesting that the two binding sites cooperate to achieve efficient ubiquitin transfer. |
| GO:0004842 ubiquitin-protein transferase activity | TAS Reactome:R-HSA-2769007 | ACCEPT | Summary: Ubiquitin-protein transferase activity (InterPro/Reactome). Reason: Correct parent of ubiquitin protein ligase activity; Reactome depicts MIB1 ubiquitinating DLL/JAG ligands. Supporting Evidence: file:human/MIB1/MIB1-uniprot.txt Positively regulates the Delta-mediated Notch signaling by ubiquitinating the intracellular domain of Delta, leading to endocytosis of Delta receptors. PMID:25747658 Individual mutation of either the N- or C-box epitope also attenuated the extent of ubiquitination, suggesting that the two binding sites cooperate to achieve efficient ubiquitin transfer. |
| GO:0004842 ubiquitin-protein transferase activity | TAS Reactome:R-HSA-2900765 | ACCEPT | Summary: Ubiquitin-protein transferase activity (InterPro/Reactome). Reason: Correct parent of ubiquitin protein ligase activity; Reactome depicts MIB1 ubiquitinating DLL/JAG ligands. Supporting Evidence: file:human/MIB1/MIB1-uniprot.txt Positively regulates the Delta-mediated Notch signaling by ubiquitinating the intracellular domain of Delta, leading to endocytosis of Delta receptors. PMID:25747658 Individual mutation of either the N- or C-box epitope also attenuated the extent of ubiquitination, suggesting that the two binding sites cooperate to achieve efficient ubiquitin transfer. |
| GO:0005515 protein binding | IPI PMID:21903422 Mapping a dynamic innate immunity protein interaction networ... | REMOVE | Summary: Interaction with TBK1/AZI2 in the innate immunity interactome. Reason: Generic protein binding; functionally MIB1 ubiquitinates TBK1, captured by ligase activity. Interaction not disputed. Supporting Evidence: PMID:21903422 Detailed mechanistic analysis defined a role for mind bomb (MIB) E3 ligases in K63-linked ubiquitination of TBK1, a kinase that phosphorylates IRF transcription factors controlling interferon production. |
| GO:0005515 protein binding | IPI PMID:21903422 Mapping a dynamic innate immunity protein interaction networ... | REMOVE | Summary: Interaction with TBK1/AZI2 in the innate immunity interactome. Reason: Generic protein binding; functionally MIB1 ubiquitinates TBK1, captured by ligase activity. Interaction not disputed. Supporting Evidence: PMID:21903422 Detailed mechanistic analysis defined a role for mind bomb (MIB) E3 ligases in K63-linked ubiquitination of TBK1, a kinase that phosphorylates IRF transcription factors controlling interferon production. |
| GO:0005515 protein binding | IPI PMID:26638075 A Dynamic Protein Interaction Landscape of the Human Centros... | REMOVE | Summary: Proximity/AP-MS interaction with PCM1. Reason: Generic protein binding; PCM1 is a substrate/partner at centriolar satellites. Supporting Evidence: PMID:26638075 we use proximity-dependent biotinylation (BioID) to map the centrosome-cilium interface |
| GO:0005515 protein binding | IPI PMID:28712572 Centriolar Satellites Control GABARAP Ubiquitination and GAB... | REMOVE | Summary: MIB1 binds GABARAP via its substrate-binding region. Reason: Generic protein binding; GABARAP is a substrate, captured by ligase activity. Supporting Evidence: PMID:28712572 GABARAP instability is mediated through the centriolar satellite E3 ligase Mib1, which interacts with GABARAP through its substrate-binding region and promotes K48-linked ubiquitination of GABARAP. |
| GO:0005515 protein binding | IPI PMID:32353859 A SARS-CoV-2 protein interaction map reveals targets for dru... | REMOVE | Summary: High-throughput interaction with a SARS-CoV-2 protein. Reason: Generic protein binding from viral interactome screens; uninformative. |
| GO:0005515 protein binding | IPI PMID:33060197 Comparative host-coronavirus protein interaction networks re... | REMOVE | Summary: High-throughput interaction with a SARS-CoV-2 protein. Reason: Generic protein binding from viral interactome screens; uninformative. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: Proximity/AP-MS interaction with PCM1. Reason: Generic protein binding; PCM1 is a substrate/partner at centriolar satellites. Supporting Evidence: PMID:26638075 we use proximity-dependent biotinylation (BioID) to map the centrosome-cilium interface |
| GO:0005515 protein binding | IPI PMID:34232536 Interactomes of SARS-CoV-2 and human coronaviruses reveal ho... | REMOVE | Summary: High-throughput interaction with a SARS-CoV-2 protein. Reason: Generic protein binding from viral interactome screens; uninformative. |
| GO:0005515 protein binding | IPI PMID:36217030 A comprehensive SARS-CoV-2-human protein-protein interactome... | REMOVE | Summary: High-throughput interaction with a SARS-CoV-2 protein. Reason: Generic protein binding from viral interactome screens; uninformative. |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: Cytoplasmic/cytosolic localization. Reason: MIB1 is a cytoplasmic E3 acting on membrane ligand tails and satellite proteins. Supporting Evidence: file:human/MIB1/MIB1-uniprot.txt Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriolar satellite |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: Cytoplasmic/cytosolic localization. Reason: MIB1 is a cytoplasmic E3 acting on membrane ligand tails and satellite proteins. Supporting Evidence: file:human/MIB1/MIB1-uniprot.txt Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriolar satellite |
| GO:0005813 centrosome | IDA PMID:21399614 Novel asymmetrically localizing components of human centroso... | KEEP AS NON CORE | Summary: Centriolar satellite/centrosome localization. Reason: Well-documented localization linked to its ciliogenesis/autophagy roles; not its Notch role. Supporting Evidence: file:human/MIB1/MIB1-uniprot.txt Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriolar satellite PMID:28712572 GABARAP instability is mediated through the centriolar satellite E3 ligase Mib1, which interacts with GABARAP through its substrate-binding region and promotes K48-linked ubiquitination of GABARAP. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2737728 | ACCEPT | Summary: Cytoplasmic/cytosolic localization. Reason: MIB1 is a cytoplasmic E3 acting on membrane ligand tails and satellite proteins. Supporting Evidence: file:human/MIB1/MIB1-uniprot.txt Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriolar satellite |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2769007 | ACCEPT | Summary: Cytoplasmic/cytosolic localization. Reason: MIB1 is a cytoplasmic E3 acting on membrane ligand tails and satellite proteins. Supporting Evidence: file:human/MIB1/MIB1-uniprot.txt Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriolar satellite |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2900765 | ACCEPT | Summary: Cytoplasmic/cytosolic localization. Reason: MIB1 is a cytoplasmic E3 acting on membrane ligand tails and satellite proteins. Supporting Evidence: file:human/MIB1/MIB1-uniprot.txt Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriolar satellite |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Plasma membrane (by similarity). Reason: MIB1 acts on ligand cytoplasmic tails at the plasma membrane. Supporting Evidence: file:human/MIB1/MIB1-uniprot.txt Localizes to the plasma membrane (By similarity). |
| GO:0006511 ubiquitin-dependent protein catabolic process | IDA PMID:23615451 The E3 ubiquitin ligase mind bomb 1 ubiquitinates and promot... | KEEP AS NON CORE | Summary: MIB1 ubiquitinates SMN and promotes its proteasomal degradation. Reason: Direct experimental evidence; a real but non-Notch activity of MIB1. Supporting Evidence: PMID:23615451 we show that the E3 ubiquitin ligase, mind bomb 1 (Mib1), interacts with and ubiquitinates SMN and facilitates its degradation. |
| GO:0006897 endocytosis | IBA GO_REF:0000033 | ACCEPT | Summary: MIB1-dependent ubiquitination drives endocytosis of Notch ligands (PTN008608909). Reason: MIB1 contributes the ubiquitin signal that triggers epsin-dependent ligand endocytosis; part of its core Notch role. Supporting Evidence: file:human/MIB1/MIB1-uniprot.txt Positively regulates the Delta-mediated Notch signaling by ubiquitinating the intracellular domain of Delta, leading to endocytosis of Delta receptors. PMID:25747658 This ubiquitination step marks the ligand proteins for epsin-dependent endocytosis, which is critical for in vivo Notch receptor activation. |
| GO:0007219 Notch signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: MIB1 acts in the signal-sending cell of canonical Notch signaling (PTN008608909). Reason: Ligand ubiquitination by MIB1 is required for ligand endocytosis and Notch activation; human MIB1 rescues fly mib1 mutants. Supporting Evidence: file:human/MIB1/MIB1-uniprot.txt Positively regulates the Delta-mediated Notch signaling by ubiquitinating the intracellular domain of Delta, leading to endocytosis of Delta receptors. PMID:25747658 This ubiquitination step marks the ligand proteins for epsin-dependent endocytosis, which is critical for in vivo Notch receptor activation. PMID:25747658 wild-type human Mib1 was sufficient for robust rescue of Wg expression along the dorsal/ventral boundary in a manner similar to fly Mib1 |
| GO:0008270 zinc ion binding | IEA GO_REF:0000002 | ACCEPT | Summary: Zinc/metal binding by RING and ZZ zinc-finger domains. Reason: Structural cofactor binding supporting E3 activity; non-core. Supporting Evidence: file:human/MIB1/MIB1-uniprot.txt EC=2.3.2.27 |
| GO:0014069 postsynaptic density | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Postsynaptic density/glutamatergic synapse (mouse Mib1). Reason: Mouse Mib1 was reported at postsynaptic densities; tissue-specific, non-core. Supporting Evidence: file:human/MIB1/MIB1-uniprot.txt Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriolar satellite |
| GO:0016567 protein ubiquitination | IBA GO_REF:0000033 | ACCEPT | Summary: Protein ubiquitination. Reason: Core process catalysed by MIB1 on Notch ligands and other substrates. Supporting Evidence: file:human/MIB1/MIB1-uniprot.txt E3 ubiquitin-protein ligase that mediates ubiquitination of Delta receptors, which act as ligands of Notch proteins. PMID:25747658 Individual mutation of either the N- or C-box epitope also attenuated the extent of ubiquitination, suggesting that the two binding sites cooperate to achieve efficient ubiquitin transfer. |
| GO:0016567 protein ubiquitination | IEA GO_REF:0000120 | ACCEPT | Summary: Protein ubiquitination. Reason: Core process catalysed by MIB1 on Notch ligands and other substrates. Supporting Evidence: file:human/MIB1/MIB1-uniprot.txt E3 ubiquitin-protein ligase that mediates ubiquitination of Delta receptors, which act as ligands of Notch proteins. PMID:25747658 Individual mutation of either the N- or C-box epitope also attenuated the extent of ubiquitination, suggesting that the two binding sites cooperate to achieve efficient ubiquitin transfer. |
| GO:0031410 cytoplasmic vesicle | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Cytoplasmic vesicle (mouse). Reason: Consistent with co-trafficking with endocytosed ligands; non-core. Supporting Evidence: file:human/MIB1/MIB1-uniprot.txt Positively regulates the Delta-mediated Notch signaling by ubiquitinating the intracellular domain of Delta, leading to endocytosis of Delta receptors. |
| GO:0034451 centriolar satellite | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: Centriolar satellite/centrosome localization. Reason: Well-documented localization linked to its ciliogenesis/autophagy roles; not its Notch role. Supporting Evidence: file:human/MIB1/MIB1-uniprot.txt Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriolar satellite PMID:28712572 GABARAP instability is mediated through the centriolar satellite E3 ligase Mib1, which interacts with GABARAP through its substrate-binding region and promotes K48-linked ubiquitination of GABARAP. |
| GO:0034451 centriolar satellite | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Centriolar satellite/centrosome localization. Reason: Well-documented localization linked to its ciliogenesis/autophagy roles; not its Notch role. Supporting Evidence: file:human/MIB1/MIB1-uniprot.txt Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriolar satellite PMID:28712572 GABARAP instability is mediated through the centriolar satellite E3 ligase Mib1, which interacts with GABARAP through its substrate-binding region and promotes K48-linked ubiquitination of GABARAP. |
| GO:0046872 metal ion binding | IEA GO_REF:0000002 | ACCEPT | Summary: Zinc/metal binding by RING and ZZ zinc-finger domains. Reason: Structural cofactor binding supporting E3 activity; non-core. Supporting Evidence: file:human/MIB1/MIB1-uniprot.txt EC=2.3.2.27 |
| GO:0061630 ubiquitin protein ligase activity | IBA GO_REF:0000033 | ACCEPT | Summary: MIB1 is a RING E3 ubiquitin ligase (PTN001197468 for the IBA; EC 2.3.2.27). Reason: Core MF; in vitro ubiquitin transfer to the JAG1 tail and ubiquitination of SMN, GABARAP and TBK1 are shown. Supporting Evidence: file:human/MIB1/MIB1-uniprot.txt E3 ubiquitin-protein ligase that mediates ubiquitination of Delta receptors, which act as ligands of Notch proteins. PMID:25747658 Individual mutation of either the N- or C-box epitope also attenuated the extent of ubiquitination, suggesting that the two binding sites cooperate to achieve efficient ubiquitin transfer. |
| GO:0061630 ubiquitin protein ligase activity | IEA GO_REF:0000003 | ACCEPT | Summary: MIB1 is a RING E3 ubiquitin ligase (PTN001197468 for the IBA; EC 2.3.2.27). Reason: Core MF; in vitro ubiquitin transfer to the JAG1 tail and ubiquitination of SMN, GABARAP and TBK1 are shown. Supporting Evidence: file:human/MIB1/MIB1-uniprot.txt E3 ubiquitin-protein ligase that mediates ubiquitination of Delta receptors, which act as ligands of Notch proteins. PMID:25747658 Individual mutation of either the N- or C-box epitope also attenuated the extent of ubiquitination, suggesting that the two binding sites cooperate to achieve efficient ubiquitin transfer. |
| GO:0098978 glutamatergic synapse | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Postsynaptic density/glutamatergic synapse (mouse Mib1). Reason: Mouse Mib1 was reported at postsynaptic densities; tissue-specific, non-core. Supporting Evidence: file:human/MIB1/MIB1-uniprot.txt Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriolar satellite |
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Download this section (compressed HTML)Q: How does MIB1 partition between Notch ligand tails at the plasma membrane and centriolar satellite substrates, and is this regulated during differentiation?
Q: Which ligand lysines are ubiquitinated by MIB1 in vivo, given that N/C-box lysine mutants retain signaling?
Experiment: Use MIB1 knockout human cells reconstituted with MZM/REP interface mutants in sender-receiver co-culture to quantify ligand endocytosis and NOTCH1 activation.
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