Ccz1 is the Drosophila ortholog of the yeast Ccz1 longin-domain protein and forms, with Mon1, the guanine nucleotide exchange factor that activates Rab7 on maturing endosomes; in metazoa the heterodimer is further bound by the scaffold subunit Bulli (RMC1). The Mon1-Ccz1 longin-domain core contacts Rab7 and promotes GDP release, and the complex is recruited and stimulated on membranes by Rab5, driving Rab5-to-Rab7 conversion. Through Rab7 activation the complex is required for endosome maturation, delivery of endocytic cargo to lysosomes and fusion of autophagosomes with lysosomes.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005085 guanyl-nucleotide exchange factor activity | IBA GO_REF:0000033 | ACCEPT | Summary: Ccz1 contributes to the Rab7 guanine nucleotide exchange factor activity of the Mon1-Ccz1(-Bulli) complex. Reason: Rab7 GEF activity resides in the Mon1-Ccz1 heterodimer (with Bulli in metazoa); the contributes_to qualifier correctly reflects that the activity belongs to the complex. Conserved from yeast Mon1-Ccz1, so the IBA/ISS rows are sound. Supporting Evidence: PMID:32499409 Both the Mon1-Ccz1 dimer and a Bulli-containing trimer display Rab7 GEF activity. PMID:37463208 This requires Rab7 activation by its specific guanine nucleotide exchange factor (GEF) Mon1-Ccz1. |
| GO:0005085 guanyl-nucleotide exchange factor activity | IDA PMID:37463208 Regulatory sites in the Mon1-Ccz1 complex control Rab5 to Ra... | ACCEPT | Summary: Ccz1 contributes to the Rab7 guanine nucleotide exchange factor activity of the Mon1-Ccz1(-Bulli) complex. Reason: Rab7 GEF activity resides in the Mon1-Ccz1 heterodimer (with Bulli in metazoa); the contributes_to qualifier correctly reflects that the activity belongs to the complex. Conserved from yeast Mon1-Ccz1, so the IBA/ISS rows are sound. Supporting Evidence: PMID:32499409 Both the Mon1-Ccz1 dimer and a Bulli-containing trimer display Rab7 GEF activity. PMID:37463208 This requires Rab7 activation by its specific guanine nucleotide exchange factor (GEF) Mon1-Ccz1. |
| GO:0005085 guanyl-nucleotide exchange factor activity | ISS GO_REF:0000024 | ACCEPT | Summary: Ccz1 contributes to the Rab7 guanine nucleotide exchange factor activity of the Mon1-Ccz1(-Bulli) complex. Reason: Rab7 GEF activity resides in the Mon1-Ccz1 heterodimer (with Bulli in metazoa); the contributes_to qualifier correctly reflects that the activity belongs to the complex. Conserved from yeast Mon1-Ccz1, so the IBA/ISS rows are sound. Supporting Evidence: PMID:32499409 Both the Mon1-Ccz1 dimer and a Bulli-containing trimer display Rab7 GEF activity. PMID:37463208 This requires Rab7 activation by its specific guanine nucleotide exchange factor (GEF) Mon1-Ccz1. |
| GO:0005829 cytosol | IDA PMID:23418349 Dmon1 controls recruitment of Rab7 to maturing endosomes in ... | ACCEPT | Summary: Ccz1 is found in the cytosol. Reason: The Mon1-Ccz1 complex is a peripheral membrane complex that cycles between the cytosol and Rab5-positive endosomal membranes; cytosolic localisation is correct, although the functional location is the endosome membrane. |
| GO:0005829 cytosol | IEA GO_REF:0000044 | ACCEPT | Summary: Ccz1 is found in the cytosol. Reason: The Mon1-Ccz1 complex is a peripheral membrane complex that cycles between the cytosol and Rab5-positive endosomal membranes; cytosolic localisation is correct, although the functional location is the endosome membrane. |
| GO:0006914 autophagy | ISS GO_REF:0000024 | ACCEPT | Summary: Autophagy, transferred from yeast Ccz1. Reason: Yeast Mon1-Ccz1 is required for autophagosome-vacuole fusion, and in Drosophila the transfer is confirmed directly by Hegedus et al. 2016 (PMID:27559127). In starved larval fat cells a Ccz1-null allele prevents Rab7 colocalisation with Atg8a-positive autophagosomes, autophagosomes and p62/Atg8a-II accumulate, and autolysosomes are absent, so Ccz1-Mon1 is required for autophagosome-lysosome fusion. The GEF performs the Rab7 recruitment/activation step on the autophagosome, so the gene does part of the work of the process rather than merely being necessary for it. The specific step is autophagosome-lysosome fusion; autophagy is a core process of Ccz1 alongside endosome maturation and is listed in core_functions. Supporting Evidence: PMID:27559127 Thus the Ccz1-Mon1-Rab7 module is required for autophagosome-lysosome fusion PMID:27559127 In contrast, the mutation of either Ccz1 or Mon1 prevented the colocalization of Atg8a with Rab7 PMID:27559127 Rab7, Ccz1, and Mon1 mutants accumulate autophagosomes and that autolysosomes are absent from these cells PMID:37216550 the assembly of RMC1 with Mon1-Ccz1 is required for cellular RAB7A activation, autophagic functions and organismal development in zebrafish |
| GO:0007034 vacuolar transport | IBA GO_REF:0000033 | ACCEPT | Summary: Vacuolar transport (IBA). Reason: Mon1-Ccz1 activation of Rab7 is required for transport to the lysosome/vacuole; consistent conserved function. Supporting Evidence: PMID:37463208 This requires Rab7 activation by its specific guanine nucleotide exchange factor (GEF) Mon1-Ccz1. |
| GO:0016192 vesicle-mediated transport | IBA GO_REF:0000033 | MODIFY | Summary: General vesicle-mediated transport. Reason: Correct but general; MODIFY to endosome to lysosome transport via multivesicular body sorting pathway, which Ccz1 already carries (IDA). Proposed replacements: endosome to lysosome transport via multivesicular body sorting pathway Supporting Evidence: PMID:37463208 This requires Rab7 activation by its specific guanine nucleotide exchange factor (GEF) Mon1-Ccz1. |
| GO:0016192 vesicle-mediated transport | IEA GO_REF:0000002 | MODIFY | Summary: General vesicle-mediated transport. Reason: Correct but general; MODIFY to endosome to lysosome transport via multivesicular body sorting pathway, which Ccz1 already carries (IDA). Proposed replacements: endosome to lysosome transport via multivesicular body sorting pathway Supporting Evidence: PMID:37463208 This requires Rab7 activation by its specific guanine nucleotide exchange factor (GEF) Mon1-Ccz1. |
| GO:0032510 endosome to lysosome transport via multivesicular body sorting pathway | IDA PMID:23418349 Dmon1 controls recruitment of Rab7 to maturing endosomes in ... | ACCEPT | Summary: Ccz1 participates in endosome-to-lysosome transport. Reason: Annotated from the Dmon1 study; Ccz1 is the obligate partner of Mon1 in the Rab7 GEF that drives this step. Supporting Evidence: PMID:23418349 loss of function of Dmon1 results in an enlargement of maturing endosomes and loss of their association with Rab7 PMID:23418349 Our results suggest that the phenotype can be explained by the loss of function of Rab7. |
| GO:0032511 late endosome to vacuole transport via multivesicular body sorting pathway | NAS PMID:32499409 A trimeric metazoan Rab7 GEF complex is crucial for endocyto... | ACCEPT | Summary: Late endosome to vacuole transport via MVB sorting. Reason: Consistent with the Rab7 GEF role of the complex in endosome maturation. Supporting Evidence: PMID:32499409 Recruitment of Rab7 to endosomes requires the Mon1-Ccz1 guanine-nucleotide-exchange factor (GEF). |
| GO:0035658 Mon1-Ccz1 complex | IBA GO_REF:0000033 | ACCEPT | Summary: Ccz1 is a subunit of the Mon1-Ccz1 complex. Reason: Direct biochemical co-purification and the cryo-EM structure of the Drosophila Mon1-Ccz1-RMC1(Bulli) trimer establish complex membership. Supporting Evidence: PMID:32499409 full function of the Drosophila Mon1-Ccz1 complex requires a third stoichiometric subunit, termed Bulli (encoded by CG8270) PMID:37216550 we report a near-atomic resolution cryogenic-electron microscopy structure of the Drosophila Mon1-Ccz1-RMC1 complex |
| GO:0035658 Mon1-Ccz1 complex | IDA PMID:37216550 Cryo-EM structure of the Mon1-Ccz1-RMC1 complex reveals mole... | ACCEPT | Summary: Ccz1 is a subunit of the Mon1-Ccz1 complex. Reason: Direct biochemical co-purification and the cryo-EM structure of the Drosophila Mon1-Ccz1-RMC1(Bulli) trimer establish complex membership. Supporting Evidence: PMID:32499409 full function of the Drosophila Mon1-Ccz1 complex requires a third stoichiometric subunit, termed Bulli (encoded by CG8270) PMID:37216550 we report a near-atomic resolution cryogenic-electron microscopy structure of the Drosophila Mon1-Ccz1-RMC1 complex |
| GO:0035658 Mon1-Ccz1 complex | IEA GO_REF:0000002 | ACCEPT | Summary: Ccz1 is a subunit of the Mon1-Ccz1 complex. Reason: Direct biochemical co-purification and the cryo-EM structure of the Drosophila Mon1-Ccz1-RMC1(Bulli) trimer establish complex membership. Supporting Evidence: PMID:32499409 full function of the Drosophila Mon1-Ccz1 complex requires a third stoichiometric subunit, termed Bulli (encoded by CG8270) PMID:37216550 we report a near-atomic resolution cryogenic-electron microscopy structure of the Drosophila Mon1-Ccz1-RMC1 complex |
| GO:0035658 Mon1-Ccz1 complex | IPI PMID:32499409 A trimeric metazoan Rab7 GEF complex is crucial for endocyto... | ACCEPT | Summary: Ccz1 is a subunit of the Mon1-Ccz1 complex. Reason: Direct biochemical co-purification and the cryo-EM structure of the Drosophila Mon1-Ccz1-RMC1(Bulli) trimer establish complex membership. Supporting Evidence: PMID:32499409 full function of the Drosophila Mon1-Ccz1 complex requires a third stoichiometric subunit, termed Bulli (encoded by CG8270) PMID:37216550 we report a near-atomic resolution cryogenic-electron microscopy structure of the Drosophila Mon1-Ccz1-RMC1 complex |
| GO:0035658 Mon1-Ccz1 complex | IPI PMID:37463208 Regulatory sites in the Mon1-Ccz1 complex control Rab5 to Ra... | ACCEPT | Summary: Ccz1 is a subunit of the Mon1-Ccz1 complex. Reason: Direct biochemical co-purification and the cryo-EM structure of the Drosophila Mon1-Ccz1-RMC1(Bulli) trimer establish complex membership. Supporting Evidence: PMID:32499409 full function of the Drosophila Mon1-Ccz1 complex requires a third stoichiometric subunit, termed Bulli (encoded by CG8270) PMID:37216550 we report a near-atomic resolution cryogenic-electron microscopy structure of the Drosophila Mon1-Ccz1-RMC1 complex |
| GO:0035658 Mon1-Ccz1 complex | ISS GO_REF:0000024 | ACCEPT | Summary: Ccz1 is a subunit of the Mon1-Ccz1 complex. Reason: Direct biochemical co-purification and the cryo-EM structure of the Drosophila Mon1-Ccz1-RMC1(Bulli) trimer establish complex membership. Supporting Evidence: PMID:32499409 full function of the Drosophila Mon1-Ccz1 complex requires a third stoichiometric subunit, termed Bulli (encoded by CG8270) PMID:37216550 we report a near-atomic resolution cryogenic-electron microscopy structure of the Drosophila Mon1-Ccz1-RMC1 complex |
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Download this section (compressed HTML)Q: Does Drosophila Ccz1 have Mon1-independent roles, or are all ccz1 loss-of-function phenotypes explained by loss of Rab7 activation?
Q: Should Mon1-Ccz1 carry GO:0061909 autophagosome-lysosome fusion? Drosophila fat-body data (PMID:27559127) show the GEF recruits Rab7 to autophagosomes and is required for their fusion with lysosomes, and another Rab GEF (C9orf72) carries the term in human, but no MON1/CCZ1 ortholog is currently annotated to it.
Experiment: Generate ccz1 null clones in fat body and nephrocytes and compare Rab7 recruitment, endosome size and autophagic flux with Mon1 mutant clones, with rescue by a Rab7 GTP-locked mutant.
Hypothesis: Ccz1 loss phenocopies Mon1 loss in endosome maturation and autophagy in fly tissues.
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Download this section (compressed HTML)Caffeine, calcium, zinc sensitivity 1 (Ccz1) encodes a protein that forms a complex with the product of Mon1 and acts as an exchange factor of the small G-protein encoded by Rab7. The Ccz1/Mon1 complex activates and recruits the product of Rab7 to the maturing endosome, where it organizes the fusion of the matured endosome with the lysosome. Ccz1/Mon1 complex loss of function results in Rab7 phenotypes.
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