Cis4 is a 732-residue multi-pass membrane protein of the cation diffusion facilitator (CDF) family, related to budding-yeast Msc2 and animal ZnT5/ZnT7 secretory-pathway zinc transporters, with about 14 predicted transmembrane helices including an N-terminal extension in front of the conserved CDF transport core. It localizes to the cis-Golgi and physically associates with a second CDF protein, Zrg17, and the two proteins act as a heteromeric unit that moves zinc out of the cytosol into the early secretory pathway. This activity matters chiefly under zinc limitation, when cis4 or zrg17 deletion raises labile cytosolic zinc; in zinc-replete cells the ER-localized CDF transporter Zhf1 dominates zinc removal from the cytosol. Loss of Cis4 causes zinc-suppressible defects attributed to impaired membrane trafficking, including a weak cell wall, reduced acid phosphatase secretion, sensitivity to FK506 and MgCl2, and synthetic growth defects with Golgi/endosome trafficking mutants, consistent with Golgi lumenal zinc being needed for normal secretory-pathway function. Transport coupling, stoichiometry and the lumenal zinc clients are not established.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000139 Golgi membrane | IDA PMID:18199682 Cation diffusion facilitator Cis4 is implicated in Golgi mem... | MODIFY | Summary: Cis4 localizes to the cis-Golgi membrane. Reason: The curator's IDA localization is correct; the same study resolves the Golgi signal to the cis compartment (functional Cis4-RFP colocalizing with a cis-Golgi marker and not a trans-Golgi marker, per the falcon summary of the full text), and the later Choi et al. study builds on that cis-Golgi assignment. GO:1990674 Golgi cis cisterna membrane is the more specific term and is already carried by the gene via IBA. Proposed replacements: Golgi cis cisterna membrane Supporting Evidence: PMID:18199682 Cis4 localized at the cis-Golgi PMID:29529046 Cis4 and Zrg17 form a heterodimeric complex that transports zinc into the cis-Golgi. file:SCHPO/cis4/cis4-deep-research-falcon.md but not with the trans-Golgi marker Krp1-GFP |
| GO:0005385 zinc ion transmembrane transporter activity | EXP PMID:29529046 Zinc transporters belonging to the Cation Diffusion Facilita... | ACCEPT | Summary: Cis4 mediates zinc transport across an organelle membrane. Reason: Zinc-dependent mutant phenotypes, interaction with Zrg17 and cytosolic zinc-sensor measurements support zinc specificity. The experiment addresses Cis4 directly, providing independent grounding for the IBA/InterPro assignment. Supporting Evidence: PMID:29529046 Cis4 and Zrg17 form a heterodimeric complex that transports zinc into the cis-Golgi. PMID:29529046 deletion of cis4 or zrg17 leads to higher levels of zinc accumulating in the cytosol under conditions of zinc deficiency |
| GO:0005385 zinc ion transmembrane transporter activity | IBA GO_REF:0000033 | ACCEPT | Summary: Cis4 mediates zinc transport across an organelle membrane. Reason: PAINT node PTN000169508 spans the Msc2/ZnT7 subfamily (PTHR45755:SF4, which contains Cis4) and the ZnT5 subfamily (SF1), with donors including budding-yeast Msc2, human ZnT5 and ZnT7 and Cis4 itself; Cis4 lies inside the clade. Its own zinc-sensor and zinc-suppression data independently confirm the inherited activity. The more specific proton-coupled antiporter activity of the SF1 ZnT5 branch was not propagated and is not asserted here. Supporting Evidence: PMID:29529046 Cis4 and Zrg17 form a heterodimeric complex that transports zinc into the cis-Golgi. PMID:29529046 deletion of cis4 or zrg17 leads to higher levels of zinc accumulating in the cytosol under conditions of zinc deficiency |
| GO:0005385 zinc ion transmembrane transporter activity | IEA GO_REF:0000002 | ACCEPT | Summary: Cis4 mediates zinc transport across an organelle membrane. Reason: Zinc-dependent mutant phenotypes, interaction with Zrg17 and cytosolic zinc-sensor measurements support zinc specificity. The experiment addresses Cis4 directly, providing independent grounding for the IBA/InterPro assignment. Supporting Evidence: PMID:29529046 Cis4 and Zrg17 form a heterodimeric complex that transports zinc into the cis-Golgi. PMID:29529046 deletion of cis4 or zrg17 leads to higher levels of zinc accumulating in the cytosol under conditions of zinc deficiency |
| GO:0005385 zinc ion transmembrane transporter activity | IMP PMID:18199682 Cation diffusion facilitator Cis4 is implicated in Golgi mem... | ACCEPT | Summary: Cis4 mediates zinc transport across an organelle membrane. Reason: Zinc-dependent mutant phenotypes, interaction with Zrg17 and cytosolic zinc-sensor measurements support zinc specificity. The experiment addresses Cis4 directly, providing independent grounding for the IBA/InterPro assignment. Supporting Evidence: PMID:29529046 Cis4 and Zrg17 form a heterodimeric complex that transports zinc into the cis-Golgi. PMID:29529046 deletion of cis4 or zrg17 leads to higher levels of zinc accumulating in the cytosol under conditions of zinc deficiency |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | UNDECIDED | Summary: An additional ER membrane pool is not established by the available target experiments. Reason: The experimentally distinguished compartments are cis-Golgi for Cis4/Zrg17 and ER for Zhf1. The UniProt ER location line carries no evidence tag, and the cis-Golgi marker used for colocalization (Rer1) itself cycles between ER and cis-Golgi, so a minor ER pool is neither shown nor excluded. The budding-yeast ortholog Msc2/Zrg17 acts in the ER, which makes an ER pool plausible but does not establish it for Cis4. Retain uncertainty. Supporting Evidence: PMID:29529046 Cis4 and Zrg17 form a heterodimeric complex that transports zinc into the cis-Golgi. |
| GO:0005794 Golgi apparatus | IBA GO_REF:0000033 | MODIFY | Summary: Cis4 is a cis-Golgi membrane transporter. Reason: The deep PAINT node PTN000169412 assertion of Golgi apparatus is correct for Cis4 but less precise than its target localization (cis-Golgi), which the shallower node PTN000169508 already captures as GO:1990674 Golgi cis cisterna membrane. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000169412 SUPPORTS TRANSFER Deep secretory-pathway CDF node; Golgi assertion is correct but coarse for Cis4. Proposed replacements: Golgi cis cisterna membrane Supporting Evidence: PMID:18199682 Cis4 localized at the cis-Golgi PMID:29529046 Cis4 and Zrg17 form a heterodimeric complex that transports zinc into the cis-Golgi. |
| GO:0005794 Golgi apparatus | IEA GO_REF:0000044 | MODIFY | Summary: Cis4 is a cis-Golgi membrane transporter. Reason: Target-specific localization is more precise than the broader compartment label. Proposed replacements: Golgi cis cisterna membrane Supporting Evidence: PMID:29529046 Cis4 and Zrg17 form a heterodimeric complex that transports zinc into the cis-Golgi. |
| GO:0006812 monoatomic cation transport | IEA GO_REF:0000002 | MODIFY | Summary: Cis4 transports zinc from cytosol into the Golgi lumen. Reason: The target studies establish substrate and transport direction; generic cation/organelle/transmembrane transport can be made specific. Proposed replacements: zinc ion import into Golgi lumen Supporting Evidence: PMID:29529046 Cis4 and Zrg17 form a heterodimeric complex that transports zinc into the cis-Golgi. |
| GO:0006829 zinc ion transport | IEA GO_REF:0000002 | MODIFY | Summary: Cis4 transports zinc from cytosol into the Golgi lumen. Reason: The target studies establish substrate and transport direction; generic cation/organelle/transmembrane transport can be made specific. Proposed replacements: zinc ion import into Golgi lumen Supporting Evidence: PMID:29529046 Cis4 and Zrg17 form a heterodimeric complex that transports zinc into the cis-Golgi. |
| GO:0006882 intracellular zinc ion homeostasis | IBA GO_REF:0000033 | ACCEPT | Summary: Cis4 maintains intracellular zinc homeostasis. Reason: Loss of Cis4 elevates cytosolic zinc under zinc limitation, demonstrating a homeostatic role through organellar import. Supporting Evidence: PMID:29529046 deletion of cis4 or zrg17 leads to higher levels of zinc accumulating in the cytosol under conditions of zinc deficiency |
| GO:0006882 intracellular zinc ion homeostasis | IDA PMID:29529046 Zinc transporters belonging to the Cation Diffusion Facilita... | ACCEPT | Summary: Cis4 maintains intracellular zinc homeostasis. Reason: Loss of Cis4 elevates cytosolic zinc under zinc limitation, demonstrating a homeostatic role through organellar import. Supporting Evidence: PMID:29529046 deletion of cis4 or zrg17 leads to higher levels of zinc accumulating in the cytosol under conditions of zinc deficiency |
| GO:0006882 intracellular zinc ion homeostasis | IEA GO_REF:0000002 | ACCEPT | Summary: Cis4 maintains intracellular zinc homeostasis. Reason: Loss of Cis4 elevates cytosolic zinc under zinc limitation, demonstrating a homeostatic role through organellar import. Supporting Evidence: PMID:29529046 deletion of cis4 or zrg17 leads to higher levels of zinc accumulating in the cytosol under conditions of zinc deficiency |
| GO:0006882 intracellular zinc ion homeostasis | IMP PMID:18199682 Cation diffusion facilitator Cis4 is implicated in Golgi mem... | ACCEPT | Summary: Cis4 maintains intracellular zinc homeostasis. Reason: Loss of Cis4 elevates cytosolic zinc under zinc limitation, demonstrating a homeostatic role through organellar import. Supporting Evidence: PMID:29529046 deletion of cis4 or zrg17 leads to higher levels of zinc accumulating in the cytosol under conditions of zinc deficiency |
| GO:0008324 monoatomic cation transmembrane transporter activity | IEA GO_REF:0000002 | MODIFY | Summary: The relevant cation is zinc. Reason: Target zinc-sensor measurements and zinc-responsive mutant phenotypes resolve the transporter substrate. Proposed replacements: zinc ion transmembrane transporter activity Supporting Evidence: PMID:29529046 Cis4 and Zrg17 form a heterodimeric complex that transports zinc into the cis-Golgi. PMID:29529046 deletion of cis4 or zrg17 leads to higher levels of zinc accumulating in the cytosol under conditions of zinc deficiency |
| GO:0016020 membrane | IEA GO_REF:0000002 | MODIFY | Summary: Cis4 is a cis-Golgi membrane transporter. Reason: Target-specific localization is more precise than the broader compartment label. Proposed replacements: Golgi cis cisterna membrane Supporting Evidence: PMID:29529046 Cis4 and Zrg17 form a heterodimeric complex that transports zinc into the cis-Golgi. |
| GO:0030003 intracellular monoatomic cation homeostasis | IEA GO_REF:0000117 | MODIFY | Summary: Cis4 contributes specifically to intracellular zinc homeostasis. Reason: The experimentally demonstrated ion and process are more precise than broad ion-homeostasis categories. Proposed replacements: intracellular zinc ion homeostasis Supporting Evidence: PMID:29529046 deletion of cis4 or zrg17 leads to higher levels of zinc accumulating in the cytosol under conditions of zinc deficiency |
| GO:0031410 cytoplasmic vesicle | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: A vesicular localization is compatible with secretory-pathway traffic but is not the established principal site. Reason: Retain the phylogenetic compartment inference as non-core; the direct target evidence establishes cis-Golgi transport and does not exclude a trafficking pool. Supporting Evidence: PMID:29529046 Cis4 and Zrg17 form a heterodimeric complex that transports zinc into the cis-Golgi. |
| GO:0055085 transmembrane transport | IEA GO_REF:0000002 | MODIFY | Summary: Cis4 transports zinc from cytosol into the Golgi lumen. Reason: The target studies establish substrate and transport direction; generic cation/organelle/transmembrane transport can be made specific. Proposed replacements: zinc ion import into Golgi lumen Supporting Evidence: PMID:29529046 Cis4 and Zrg17 form a heterodimeric complex that transports zinc into the cis-Golgi. |
| GO:0062111 zinc ion import into organelle | IDA PMID:29529046 Zinc transporters belonging to the Cation Diffusion Facilita... | MODIFY | Summary: Cis4 transports zinc from cytosol into the Golgi lumen. Reason: The target studies establish substrate and transport direction; generic cation/organelle/transmembrane transport can be made specific. Proposed replacements: zinc ion import into Golgi lumen Supporting Evidence: PMID:29529046 Cis4 and Zrg17 form a heterodimeric complex that transports zinc into the cis-Golgi. |
| GO:0098771 inorganic ion homeostasis | IEA GO_REF:0000117 | MODIFY | Summary: Cis4 contributes specifically to intracellular zinc homeostasis. Reason: The experimentally demonstrated ion and process are more precise than broad ion-homeostasis categories. Proposed replacements: intracellular zinc ion homeostasis Supporting Evidence: PMID:29529046 deletion of cis4 or zrg17 leads to higher levels of zinc accumulating in the cytosol under conditions of zinc deficiency |
| GO:1904257 zinc ion import into Golgi lumen | IBA GO_REF:0000033 | ACCEPT | Summary: Cis4 imports zinc into the Golgi lumen. Reason: The cis-Golgi localization, Zrg17 complex and mutant zinc-homeostasis data jointly establish the physiological direction and destination. Supporting Evidence: PMID:29529046 Cis4 and Zrg17 form a heterodimeric complex that transports zinc into the cis-Golgi. PMID:29529046 deletion of cis4 or zrg17 leads to higher levels of zinc accumulating in the cytosol under conditions of zinc deficiency |
| GO:1904257 zinc ion import into Golgi lumen | IMP PMID:18199682 Cation diffusion facilitator Cis4 is implicated in Golgi mem... | ACCEPT | Summary: Cis4 imports zinc into the Golgi lumen. Reason: The cis-Golgi localization, Zrg17 complex and mutant zinc-homeostasis data jointly establish the physiological direction and destination. Supporting Evidence: PMID:29529046 Cis4 and Zrg17 form a heterodimeric complex that transports zinc into the cis-Golgi. PMID:29529046 deletion of cis4 or zrg17 leads to higher levels of zinc accumulating in the cytosol under conditions of zinc deficiency |
| GO:1990674 Golgi cis cisterna membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Cis4 acts in the cis-Golgi membrane. Reason: The target localization agrees with the phylogenetic inference; this is not a generic CDF-family compartment transfer. Supporting Evidence: PMID:29529046 Cis4 and Zrg17 form a heterodimeric complex that transports zinc into the cis-Golgi. |
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Download this section (compressed HTML)Q: Does Cis4 itself carry the zinc-binding transport site, or is Zrg17 (or both) the translocating subunit in the Cis4/Zrg17 heteromer, as debated for the mammalian ZnT5/ZnT6 pair?
Q: Is there a functional ER pool of Cis4 (as for the budding-yeast Msc2/Zrg17 complex), or is the UniProt ER membrane location solely a reflection of ER-Golgi cycling?
Q: Which cis-Golgi lumenal zinc-dependent clients (e.g. phosphatases, GPI-anchor remodelling enzymes) require Cis4-supplied zinc?
Experiment: Reconstitute purified Cis4/Zrg17 in proteoliposomes and measure zinc flux and proton coupling, with conserved transmembrane His/Asp site mutants in each subunit.
Experiment: Measure lumenal Golgi and ER zinc with organelle-targeted zinc FRET sensors in cis4 and zrg17 deletion strains under zinc-limited conditions.
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