Cytosolic iron-sulfur protein assembly (CIA) in human cells

The cytosolic iron-sulfur protein assembly (CIA) machinery builds [4Fe-4S] clusters in the cytosol and inserts them into cytosolic and nuclear apoproteins, including enzymes of DNA replication and repair, purine metabolism and iron regulation (IRP1). It depends on the mitochondrial iron-sulfur cluster (ISC) machinery, which produces a still-unidentified sulfur-containing compound that the inner-membrane ABC transporter ABCB7 exports to the cytosol. In the cytosol, the NADPH-dependent diflavin reductase NDOR1 passes electrons to the [2Fe-2S] cluster of anamorsin (CIAPIN1). A heterotetrameric scaffold of the P-loop NTPases NUBP1 and NUBP2 assembles [4Fe-4S] clusters. CIAO3 (NARFL) and the CIA targeting complex then transfer the clusters to recipient apoproteins. The targeting complex has a core of the WD40 protein CIAO1, the MIP18-family protein CIAO2B and the HEAT-repeat adaptor MMS19, which binds most client apoproteins. CIAO1 paired with the paralog CIAO2A instead matures IRP1. The client apoproteins are substrates of the pathway, not parts of the machinery.

Derived from RGD PW:0002636 (cytosolic iron-sulfur cluster protein assembly pathway), whose nine RGD-curated human genes are CIAO1, CIAO2A, CIAO2B, CIAO3, CIAPIN1, MMS19, NDOR1, NUBP1 and NUBP2; all nine are parts here. GO term check: GO release 2026-07-26 has no process term for the cytosolic machinery as such (no "cytosolic iron-sulfur cluster assembly" or CIA pathway term; the former maturation term GO:0097428 is obsolete). It does have the two CIA complexes as cellular components (GO:1904564 scaffold, GO:0097361 targeting complex), which are used as node concepts. The project maps PW:0002636 to GO:0016226 iron-sulfur cluster assembly only as a broad match; the module concept is its child GO:0044572 [4Fe-4S] cluster assembly with cytosol as context, matching how the fly and fission yeast GO-CAMs type their CIA activities. Boundary decisions. (1) Upstream: the mitochondrial ISC core is included by module_ref to mitochondrial_iron_sulfur_cluster_assembly, and ABCB7 export is written as its own optional step because that module does not model export (its notes list ABCB7 as not yet modelled). Both are optional parts so this module's satisfiability rests on the cytosolic steps; the RGD export pathway (PW:0002637, which adds glutathione and GFER) and the mitochondrial biogenesis pathway (PW:0002635) are separate RGD terms and are not claimed as evidence here. (2) Downstream: client apoproteins (DNA polymerases, helicases, primase, PPAT, IRP1/ACO1, CIAO3 itself possibly) are substrates and are named only as function targets, not parts; by the substrate-versus-participant rule they do not carry the process. IRP2 stabilization by CIAO2A is iron regulation, not cluster assembly, and is described only in prose. (3) GLRX3-BOLA2 [2Fe-2S] delivery to NUBP1 and the CIAO3-independent routes proposed in some systems are not modelled; GLRX3 is not in the RGD gene set. (4) The NUBP1-NUBP2 scaffold is given the cluster-binding function that NUBP1 carries by IDA, not the ATP-dependent FeS chaperone function used in the fission yeast model, because no human annotation supports ATP-dependent transfer. (5) CIAO2B and CIAO3 have no molecular function asserted (GOA has only protein binding); CIAPIN1 electron transfer activity is asserted from the cached electron-transfer experiments although GOA has it only by IEA. (6) CIAO2A is modelled as an optional single-client branch rather than as an alternative to CIAO2B, since cells need both. GO-CAM links point to the Drosophila iron-sulfur model (gomodel:6796b94c00000657, behind modules/dmel_iron_sulfur_cluster_assembly, the fly counterpart of this module and of the mitochondrial ISC module) and the fission yeast model (gomodel:6690711d00000331); no human GO-CAM in gocams/index.tsv contains a CIA member, and the seed recorded no best GO-CAM. The two orthologous models type the targeting complex differently (chaperone in fly, iron-sulfur transferase in fission yeast).