Cis4 is a CDF-family zinc transporter that forms a heteromeric complex with Zrg17 in the cis-Golgi membrane. It transfers zinc from the cytosol into the secretory pathway, particularly under zinc-limiting conditions, and thereby supports intracellular zinc balance and Golgi-dependent protein trafficking. Its compartment and low-zinc role differ from the ER zinc transporter Zhf1.
The 2008 target study identifies Cis4 localization at cis-Golgi and its interaction with Zrg17. The 2018 full-text study uses zinc-sensitive FRET sensors in defined cis4/zrg17/zhf1 mutants: Cis4/Zrg17 is important during zinc limitation; ER-localized Zhf1 is important when zinc is abundant. Thus zinc specificity is supported by target physiology rather than a generic CDF family label. The ER IEA assertion remains unresolved as a possible additional pool; no exclusion experiment establishes that Cis4 can never reside in ER.
These experiments do not establish exact transport coupling, affinity, stoichiometry or complete alternative-metal exclusion. Golgi trafficking and cell-wall phenotypes are downstream consequences of zinc partitioning, not evidence that Cis4 transports magnesium or directly assembles GPI anchors. Falcon agrees on these distinctions; its numerical phenotypes are not copied into curated fields without source verification.
Exact retained output. These are name/location claims, not emitted GO/EC predictions. CNN denotes overlap with existing supported annotation; it does not establish literal membership in the training set.
| Claim type | Verbatim output | Assessment | Evidence and interpretation |
|---|---|---|---|
| name | Zinc transporter | LSP | The correct broad name omits experimentally established cis-Golgi import with Zrg17 and its low-zinc role. Target zinc-sensor and localization experiments establish zinc specificity (PMID:18199682; PMID:29529046). |
| location | Membrane | LSP | A correct but broad compartment: the target is a cis-Golgi membrane transporter. This conclusion comes from target localization and zinc-transport physiology, not simply from a membrane-domain default (PMID:18199682; PMID:29529046). |
PMID:29529046(https://pubmed.ncbi.nlm.nih.gov/29529046/):
Cis4 and Zrg17 form a heterodimeric complex that
transports zinc into the cis-Golgi.
PMID:29529046(https://pubmed.ncbi.nlm.nih.gov/29529046/):
deletion of cis4 or
zrg17 leads to higher levels of zinc accumulating in the cytosol under
conditions of zinc deficiency
The genuine Falcon report is retained with its provider metadata and artifact. Its conclusions were checked against the target record, exact accession and primary sources described above. Scientific uncertainties are recorded as UNC/UNDECIDED findings rather than a request for another reviewer to perform this assessment.
Identity. Q9HGQ3 is the reviewed, canonical, full-length UniProt entry for cis4 (SPAC17D4.03c),
732 aa, 14 predicted TM segments (UniProt FT TRANSMEM 52-72 ... 615-635), with the Cation_efflux
(PF01545) core and the Msc2-like signature (IPR045316). It is not an isoform, fragment or alternative
gene model; no domain or region is missing relative to the gene's product.
Evolutionary placement. PANTHER PTHR45755 ("FAMILY NOT NAMED"), subfamily SF4 ("ZINC TRANSPORTER 7").
SF4 also holds budding-yeast Msc2 (Q03455) and vertebrate ZnT7/SLC30A7; vertebrate ZnT5/SLC30A5 sits in
SF1 (interpro/panther/PTHR45755/PTHR45755-entries.csv). Note that Cis4 and Msc2 have the long
N-terminal TM extension seen in ZnT5 rather than the short ZnT7 architecture, yet PANTHER groups them with
ZnT7; the subfamily name is therefore not a functional statement about Cis4. The IBA terms for zinc
transporter activity, zinc homeostasis, zinc import into Golgi lumen and Golgi cis cisterna membrane come
from PTN000169508, which spans SF1+SF4 and includes Cis4, Msc2, ZnT5 and ZnT7 as donors; the
Golgi apparatus and cytoplasmic vesicle IBAs come from the deeper PTN000169412. PAINT did not propagate
ZnT5's proton-coupled antiporter activity; I treat that as deliberate and do not assert it.
Literature. PMID:18199682 (abstract only cached; PMC full text blocked by captcha here): cis4-1 from
an FK506/MgCl2 sensitivity screen; zinc suppresses phenotypes; Cis4 and Zrg17 physically interact and
share nonadditive phenotypes; Cis4 localizes to cis-Golgi (falcon summary of full text: Cis4-RFP
colocalizes with Rer1-GFP but not Krp1-GFP; MSC2+ZRG17 coexpression rescues). PMID:29529046 (full
text): ZapCY FRET sensors show cis4Δ/zrg17Δ accumulate cytosolic zinc in zinc deficiency, zhf1Δ when
zinc replete. Trafficking/cell-wall/acid-phosphatase/GPI-protein links (incl. Jaiseng 2012,
doi:10.1371/journal.pone.0041946, not cached) are downstream consequences of zinc supply; no process term
for membrane trafficking or GPI-anchor biosynthesis is proposed.
Annotation decisions (re-examined, essentially unchanged). Zinc transporter activity (EXP, IMP,
IBA, IEA) ACCEPT; intracellular zinc ion homeostasis (IDA, IMP, IBA, IEA) ACCEPT; zinc ion import into
Golgi lumen (IMP, IBA) ACCEPT; Golgi cis cisterna membrane (IBA) ACCEPT. Generic transport/cation/
homeostasis/membrane/Golgi terms MODIFY to the specific supported terms; zinc ion import into organelle
(IDA) MODIFY to its descendant GO:1904257. ER membrane (UniProt SubCell, no evidence tag) stays
UNDECIDED: Rer1 cycles ER-cis-Golgi and the Msc2 ortholog acts in the ER, so an ER pool is plausible
but unshown. Cytoplasmic vesicle (deep IBA) KEEP_AS_NON_CORE.
Changes made. Rewrote description (architecture, Zrg17 heteromer, low-zinc role, trafficking
phenotypes as downstream); added PMID:18199682 abstract quotes as support for localization and
interaction; expanded IBA reasons with node placement; added propagation_review on the Golgi apparatus
IBA; added reference_review for all references and a falcon file reference; added suggested questions and
experiments. No references removed, no files deleted.
Next relative. Budding-yeast MSC2 (Q03455): same PANTHER subfamily SF4, a donor to PTN000169508, the
Zrg17-partnered ortholog (ER zinc import with Zrg17), and it complements cis4 with ZRG17. No review in
genes/yeast/. Partner Zrg17 (SPBC16E9.14c) is also unreviewed. No module in modules/ covers
Cis4/Zrg17 or secretory-pathway zinc import.