CISD2 (NAF-1/Miner1) is a small membrane-associated homodimeric protein that coordinates redox-active [2Fe-2S] clusters through its CDGSH domain. Its cytosolic domain can transfer a cluster to an apo-acceptor protein, and binding to BCL2 links it to restraint of Beclin 1-dependent autophagy at the endoplasmic reticulum. Human cell studies support endoplasmic reticulum localization; endogenous mouse tissue fractionation places Cisd2 predominantly in mitochondria, enriched at the outer membrane, with a smaller ER pool. CISD2 helps maintain organelle homeostasis, and loss of function causes Wolfram syndrome 2. Effects on calcium handling depend on the cellular context and the associated BCL2 complexes.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000422 autophagy of mitochondrion | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: The damage-associated phenotype does not establish participation in mitochondrial autophagy. Reason: The authenticated mouse Cisd2 donor has a genuine IMP annotation from PMID:19451219. Its knockout causes mitochondrial damage, autophagic vacuoles and increased LC3-II/LC3-I; the Results interpret clearance of damaged organelles as a response to mitochondrial dysfunction. GO:0000422 names mitochondrial delivery and degradation by autophagy, but these experiments do not establish a step performed by Cisd2 in that process. The preserved involved_in assertion therefore exceeds the demonstrated role. Increased autophagy after loss also does not by itself establish specific negative regulation of mitophagy. The separate BCL2–BECN1 interaction and starvation-flux experiments in PMID:20010695 support the existing general negative-regulation refinement, not a mitochondrial-selective replacement here. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: PANTHER:PTN008550313 UNRESOLVED The exact mouse donor and its experimental annotation are authentic. The inspected primary evidence establishes mitochondrial damage with increased autophagy, rather than a demonstrated mitochondrial-autophagy step performed by Cisd2. Historical IBD evidence, node placement and alignment remain uninspected, so the ancestral source cannot be classified confidently; this is a role-scoping objection, not a claim of wrong orthology, donor-count weakness or erroneous phylogeny. |
| GO:0000422 autophagy of mitochondrion | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: The damage-associated phenotype does not establish participation in mitochondrial autophagy. Reason: The authenticated mouse Cisd2 donor has a genuine IMP annotation from PMID:19451219. Its knockout causes mitochondrial damage, autophagic vacuoles and increased LC3-II/LC3-I; the Results interpret clearance of damaged organelles as a response to mitochondrial dysfunction. GO:0000422 names mitochondrial delivery and degradation by autophagy, but these experiments do not establish a step performed by Cisd2 in that process. The preserved involved_in assertion therefore exceeds the demonstrated role. Increased autophagy after loss also does not by itself establish specific negative regulation of mitophagy. The separate BCL2–BECN1 interaction and starvation-flux experiments in PMID:20010695 support the existing general negative-regulation refinement, not a mitochondrial-selective replacement here. |
| GO:0003723 RNA binding | HDA PMID:22658674 Insights into RNA biology from an atlas of mammalian mRNA-bi... | KEEP AS NON CORE | Summary: CISD2 is a positive HeLa mRNA-interactome capture hit. Reason: Original Castello Table S1, HeLa mRNA interactome sheet row 526, identifies CISD2 in both crosslinked and control samples. Ion-count enrichment passes the study threshold (adjusted p 0.0021476), whereas the spectral-count/DESeq test does not (0.9304). Control detection and disagreement between the two tests limit confidence in the individual hit; the study nevertheless explicitly includes proteins enriched by either analysis. Retain this gene-level capture evidence outside the core without inferring an RNA target, product-specific activity or RNA-processing role. A known RNA-binding fold is not required by the term definition. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:20010695 Antagonism of Beclin 1-dependent autophagy by BCL-2 at the e... | MODIFY | Summary: Specify the experimentally mapped BCL2 BH4 interaction. Reason: The original paper demonstrates endogenous association and a GST-domain pull-down. Independent peptide-array and solution experiments map CISD2 binding to BCL2 BH4 and part of BH3; BH4 peptide binding also changes cluster stability and transfer. Use the directly supported BH4-domain term without treating this interaction as CISD2 anti-apoptotic activity or transferring the site mapping to BCLXL. Proposed replacements: BH4 domain binding |
| GO:0005515 protein binding | IPI PMID:20010695 Antagonism of Beclin 1-dependent autophagy by BCL-2 at the e... | KEEP AS NON CORE | Summary: Retain the BCLXL association without an untested domain assignment. Reason: The original endogenous co-immunoprecipitation supports association with BCLXL. The experimentally mapped BCL2 BH4/BH3 interface does not establish the corresponding contact on BCLXL, and this result alone does not define a separate CISD2 physiological activity. Together with the separate BCL2 and BCL2L2 observations, this is corroborating BCL2-family interaction context; it does not establish a shared binding site or the same regulatory effect for each partner. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:20010695 Antagonism of Beclin 1-dependent autophagy by BCL-2 at the e... | MODIFY | Summary: Specify association with the IP3R1 transmembrane calcium transporter. Reason: The original co-immunoprecipitation places CISD2 in an IP3R1-containing complex. IP3R1 is an authenticated transmembrane calcium channel, fitting transmembrane transporter binding. Preserve the association-level assay scope: an isolated binary interface or a direct channel-gating mechanism was not established. Proposed replacements: transmembrane transporter binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the SMIM1 screen interaction outside the core. Reason: 3 exact source/target/partner records support the tagged yeast two-hybrid association with SMIM1 (B2RUZ4). The positive pair is retained, but an evidence-backed, useful specific binding class or physiological CISD2 mechanism is not established for this interaction. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the C2CD2L screen interaction outside the core. Reason: 3 exact source/target/partner records support the tagged yeast two-hybrid association with C2CD2L (O14523). The positive pair is retained, but an evidence-backed, useful specific binding class or physiological CISD2 mechanism is not established for this interaction. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the CDIPT screen interaction outside the core. Reason: 3 exact source/target/partner records support the tagged yeast two-hybrid association with CDIPT (O14735). The positive pair is retained, but an evidence-backed, useful specific binding class or physiological CISD2 mechanism is not established for this interaction. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MODIFY | Summary: Specify the verified BET1 partner class at screening-assay scope. Reason: The exact PMID:32296183 records support a tagged yeast two-hybrid interaction with BET1 (O15155), and the authenticated partner is a vesicular SNARE. The specific binding class is supported at screening-assay scope; its physiological consequence for CISD2 remains unestablished. Proposed replacements: SNARE binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MODIFY | Summary: Specify the verified STX7 partner class at screening-assay scope. Reason: The exact PMID:32296183 records support a tagged yeast two-hybrid interaction with STX7 (O15400), and the authenticated partner is a syntaxin. The specific binding class is supported at screening-assay scope; its physiological consequence for CISD2 remains unestablished. Proposed replacements: syntaxin binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MODIFY | Summary: Specify the verified GPR37L1 partner class at screening-assay scope. Reason: The exact PMID:32296183 records support a tagged yeast two-hybrid interaction with GPR37L1 (O60883), and the authenticated partner is a G protein-coupled receptor. The specific binding class is supported at screening-assay scope; its physiological consequence for CISD2 remains unestablished. Proposed replacements: G protein-coupled receptor binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MODIFY | Summary: Specify the verified VAMP4 partner class at screening-assay scope. Reason: The exact PMID:32296183 records support a tagged yeast two-hybrid interaction with VAMP4 (O75379), and the authenticated partner is a vesicular SNARE. The specific binding class is supported at screening-assay scope; its physiological consequence for CISD2 remains unestablished. Proposed replacements: SNARE binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the LEPROTL1 screen interaction outside the core. Reason: 3 exact source/target/partner records support the tagged yeast two-hybrid association with LEPROTL1 (O95214). The positive pair is retained, but an evidence-backed, useful specific binding class or physiological CISD2 mechanism is not established for this interaction. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the BMP10 screen interaction outside the core. Reason: 3 exact source/target/partner records support the tagged yeast two-hybrid association with BMP10 (O95393). The positive pair is retained, but an evidence-backed, useful specific binding class or physiological CISD2 mechanism is not established for this interaction. The recorded protein construct does not establish binding to a processed mature signaling peptide. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the GAST screen interaction outside the core. Reason: 3 exact source/target/partner records support the tagged yeast two-hybrid association with GAST (P01350). The positive pair is retained, but an evidence-backed, useful specific binding class or physiological CISD2 mechanism is not established for this interaction. The recorded protein construct does not establish binding to a processed mature signaling peptide. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MODIFY | Summary: Specify the verified MIP/AQP0 partner class at screening-assay scope. Reason: The exact PMID:32296183 records support a tagged yeast two-hybrid interaction with MIP/AQP0 (P30301), and the authenticated partner is a transmembrane water channel. The specific binding class is supported at screening-assay scope; its physiological consequence for CISD2 remains unestablished. Proposed replacements: transmembrane transporter binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the NSG1 screen interaction outside the core. Reason: 3 exact source/target/partner records support the tagged yeast two-hybrid association with NSG1 (P42857). The positive pair is retained, but an evidence-backed, useful specific binding class or physiological CISD2 mechanism is not established for this interaction. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the KIR2DL3 screen interaction outside the core. Reason: 3 exact source/target/partner records support the tagged yeast two-hybrid association with KIR2DL3 (P43628). The positive pair is retained, but an evidence-backed, useful specific binding class or physiological CISD2 mechanism is not established for this interaction. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the IER3 screen interaction outside the core. Reason: 3 exact source/target/partner records support the tagged yeast two-hybrid association with IER3 (P46695). The positive pair is retained, but an evidence-backed, useful specific binding class or physiological CISD2 mechanism is not established for this interaction. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the TTPA screen interaction outside the core. Reason: 5 exact source/target/partner records support the tagged yeast two-hybrid association with TTPA (P49638). The positive pair is retained, but an evidence-backed, useful specific binding class or physiological CISD2 mechanism is not established for this interaction. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the EMD screen interaction outside the core. Reason: 3 exact source/target/partner records support the tagged yeast two-hybrid association with EMD (P50402). The positive pair is retained, but an evidence-backed, useful specific binding class or physiological CISD2 mechanism is not established for this interaction. Emerin promotes nuclear actin organization and binds actin/tubulin; these facts do not by themselves establish the assayed partner as a cytoskeletal protein component for GO:0008092. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the CLDN10 screen interaction outside the core. Reason: 3 exact source/target/partner records support the tagged yeast two-hybrid association with CLDN10 (P78369). The positive pair is retained, but an evidence-backed, useful specific binding class or physiological CISD2 mechanism is not established for this interaction. Claudin-10 forms paracellular channels between cells; this does not establish the transmembrane-transporter class defined by movement across a membrane. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the EHHADH screen interaction outside the core. Reason: 3 exact source/target/partner records support the tagged yeast two-hybrid association with EHHADH (Q08426). The positive pair is retained, but an evidence-backed, useful specific binding class or physiological CISD2 mechanism is not established for this interaction. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the TMEM187 screen interaction outside the core. Reason: 3 exact source/target/partner records support the tagged yeast two-hybrid association with TMEM187 (Q14656). The positive pair is retained, but an evidence-backed, useful specific binding class or physiological CISD2 mechanism is not established for this interaction. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the RTP2 screen interaction outside the core. Reason: 3 exact source/target/partner records support the tagged yeast two-hybrid association with RTP2 (Q5QGT7). The positive pair is retained, but an evidence-backed, useful specific binding class or physiological CISD2 mechanism is not established for this interaction. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the PLPP4 screen interaction outside the core. Reason: 3 exact source/target/partner records support the tagged yeast two-hybrid association with PLPP4 (Q5VZY2). The positive pair is retained, but an evidence-backed, useful specific binding class or physiological CISD2 mechanism is not established for this interaction. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the SNORC screen interaction outside the core. Reason: 3 exact source/target/partner records support the tagged yeast two-hybrid association with SNORC (Q6UX34). The positive pair is retained, but an evidence-backed, useful specific binding class or physiological CISD2 mechanism is not established for this interaction. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the LRP10 screen interaction outside the core. Reason: 3 exact source/target/partner records support the tagged yeast two-hybrid association with LRP10 (Q7Z4F1). The positive pair is retained, but an evidence-backed, useful specific binding class or physiological CISD2 mechanism is not established for this interaction. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the TSPAN33 screen interaction outside the core. Reason: 3 exact source/target/partner records support the tagged yeast two-hybrid association with TSPAN33 (Q86UF1). The positive pair is retained, but an evidence-backed, useful specific binding class or physiological CISD2 mechanism is not established for this interaction. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MODIFY | Summary: Specify the verified STX12 partner class at screening-assay scope. Reason: The exact PMID:32296183 records support a tagged yeast two-hybrid interaction with STX12 (Q86Y82), and the authenticated partner is a syntaxin. The specific binding class is supported at screening-assay scope; its physiological consequence for CISD2 remains unestablished. Proposed replacements: syntaxin binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the VKORC1L1 screen interaction outside the core. Reason: 3 exact source/target/partner records support the tagged yeast two-hybrid association with VKORC1L1 (Q8N0U8). The positive pair is retained, but an evidence-backed, useful specific binding class or physiological CISD2 mechanism is not established for this interaction. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the TMEM86A screen interaction outside the core. Reason: 3 exact source/target/partner records support the tagged yeast two-hybrid association with TMEM86A (Q8N2M4). The positive pair is retained, but an evidence-backed, useful specific binding class or physiological CISD2 mechanism is not established for this interaction. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the GALNT15 screen interaction outside the core. Reason: 3 exact source/target/partner records support the tagged yeast two-hybrid association with GALNT15 (Q8N3T1). The positive pair is retained, but an evidence-backed, useful specific binding class or physiological CISD2 mechanism is not established for this interaction. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the SERP2 screen interaction outside the core. Reason: 3 exact source/target/partner records support the tagged yeast two-hybrid association with SERP2 (Q8N6R1). The positive pair is retained, but an evidence-backed, useful specific binding class or physiological CISD2 mechanism is not established for this interaction. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the NRAC screen interaction outside the core. Reason: 3 exact source/target/partner records support the tagged yeast two-hybrid association with NRAC (Q8N912). The positive pair is retained, but an evidence-backed, useful specific binding class or physiological CISD2 mechanism is not established for this interaction. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the BTN2A2 screen interaction outside the core. Reason: 3 exact source/target/partner records support the tagged yeast two-hybrid association with BTN2A2 (Q8WVV5). The positive pair is retained, but an evidence-backed, useful specific binding class or physiological CISD2 mechanism is not established for this interaction. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the ARLN screen interaction outside the core. Reason: 3 exact source/target/partner records support the tagged yeast two-hybrid association with ARLN (Q8WVX3-2). The positive pair is retained, but an evidence-backed, useful specific binding class or physiological CISD2 mechanism is not established for this interaction. The recorded Q8WVX3-2 sufficient region is 134–199; no complete-product activity is inferred. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the NRG4 screen interaction outside the core. Reason: 3 exact source/target/partner records support the tagged yeast two-hybrid association with NRG4 (Q8WWG1). The positive pair is retained, but an evidence-backed, useful specific binding class or physiological CISD2 mechanism is not established for this interaction. The recorded protein construct does not establish binding to a processed mature signaling peptide. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MODIFY | Summary: Specify the verified SLC13A3 partner class at screening-assay scope. Reason: The exact PMID:32296183 records support a tagged yeast two-hybrid interaction with SLC13A3 (Q8WWT9), and the authenticated partner is a sodium/dicarboxylate transmembrane cotransporter. The specific binding class is supported at screening-assay scope; its physiological consequence for CISD2 remains unestablished. Proposed replacements: transmembrane transporter binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the POMGNT1 screen interaction outside the core. Reason: 3 exact source/target/partner records support the tagged yeast two-hybrid association with POMGNT1 (Q8WZA1). The positive pair is retained, but an evidence-backed, useful specific binding class or physiological CISD2 mechanism is not established for this interaction. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the BCL2L2 screen interaction outside the core. Reason: Three exact source/target/partner records support the tagged yeast two-hybrid association with BCL2L2/BCL-w (Q92843). This adds BCL2-family interaction context alongside BCL2 and BCLXL, but neither the BCL2 BH4/BH3 mapping nor its autophagy-regulatory mechanism transfers to BCL2L2 from this screen. Retain the supported pair outside the core. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MODIFY | Summary: Specify the verified SLC35B4 partner class at screening-assay scope. Reason: The exact PMID:32296183 records support a tagged yeast two-hybrid interaction with SLC35B4 (Q969S0), and the authenticated partner is a nucleotide-sugar transmembrane transporter. The specific binding class is supported at screening-assay scope; its physiological consequence for CISD2 remains unestablished. Proposed replacements: transmembrane transporter binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the FAM241B screen interaction outside the core. Reason: 3 exact source/target/partner records support the tagged yeast two-hybrid association with FAM241B (Q96D05-2). The positive pair is retained, but an evidence-backed, useful specific binding class or physiological CISD2 mechanism is not established for this interaction. The recorded Q96D05-2 sufficient region is 43–163. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the YIPF6 screen interaction outside the core. Reason: 3 exact source/target/partner records support the tagged yeast two-hybrid association with YIPF6 (Q96EC8). The positive pair is retained, but an evidence-backed, useful specific binding class or physiological CISD2 mechanism is not established for this interaction. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the PLPPR2 screen interaction outside the core. Reason: 3 exact source/target/partner records support the tagged yeast two-hybrid association with PLPPR2 (Q96GM1). The positive pair is retained, but an evidence-backed, useful specific binding class or physiological CISD2 mechanism is not established for this interaction. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the RUSF1 screen interaction outside the core. Reason: 3 exact source/target/partner records support the tagged yeast two-hybrid association with RUSF1 (Q96GQ5). The positive pair is retained, but an evidence-backed, useful specific binding class or physiological CISD2 mechanism is not established for this interaction. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the SEC22A screen interaction outside the core. Reason: 3 exact source/target/partner records support the tagged yeast two-hybrid association with SEC22A (Q96IW7). The positive pair is retained, but an evidence-backed, useful specific binding class or physiological CISD2 mechanism is not established for this interaction. SEC22A has a longin domain and a current inferred SNAP-receptor annotation, but primary sequence analysis distinguishes it from SNARE-domain-containing SEC22B; the family name alone does not justify SNARE binding. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MODIFY | Summary: Specify the verified AQP10 partner class at screening-assay scope. Reason: The exact PMID:32296183 records support a tagged yeast two-hybrid interaction with AQP10 (Q96PS8), and the authenticated partner is a transmembrane aquaglyceroporin. The specific binding class is supported at screening-assay scope; its physiological consequence for CISD2 remains unestablished. Proposed replacements: transmembrane transporter binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the PNKP screen interaction outside the core. Reason: 3 exact source/target/partner records support the tagged yeast two-hybrid association with PNKP (Q96T60). The positive pair is retained, but an evidence-backed, useful specific binding class or physiological CISD2 mechanism is not established for this interaction. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the CYBC1 screen interaction outside the core. Reason: 3 exact source/target/partner records support the tagged yeast two-hybrid association with CYBC1 (Q9BQA9). The positive pair is retained, but an evidence-backed, useful specific binding class or physiological CISD2 mechanism is not established for this interaction. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the APOL2 screen interaction outside the core. Reason: 3 exact source/target/partner records support the tagged yeast two-hybrid association with APOL2 (Q9BQE5). The positive pair is retained, but an evidence-backed, useful specific binding class or physiological CISD2 mechanism is not established for this interaction. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the TMEM43 screen interaction outside the core. Reason: 3 exact source/target/partner records support the tagged yeast two-hybrid association with TMEM43 (Q9BTV4). The positive pair is retained, but an evidence-backed, useful specific binding class or physiological CISD2 mechanism is not established for this interaction. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the TMEM243 screen interaction outside the core. Reason: 3 exact source/target/partner records support the tagged yeast two-hybrid association with TMEM243 (Q9BU79). The positive pair is retained, but an evidence-backed, useful specific binding class or physiological CISD2 mechanism is not established for this interaction. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the CFHR5 screen interaction outside the core. Reason: 3 exact source/target/partner records support the tagged yeast two-hybrid association with CFHR5 (Q9BXR6). The positive pair is retained, but an evidence-backed, useful specific binding class or physiological CISD2 mechanism is not established for this interaction. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the THSD7B screen interaction outside the core. Reason: 3 exact source/target/partner records support the tagged yeast two-hybrid association with THSD7B (Q9C0I4). The positive pair is retained, but an evidence-backed, useful specific binding class or physiological CISD2 mechanism is not established for this interaction. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the NAPB screen interaction outside the core. Reason: 3 exact source/target/partner records support the tagged yeast two-hybrid association with NAPB (Q9H115). The positive pair is retained, but an evidence-backed, useful specific binding class or physiological CISD2 mechanism is not established for this interaction. NAPB is a SNARE-associated adaptor, which is not itself sufficient to classify it as a SNARE. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the HHATL screen interaction outside the core. Reason: 3 exact source/target/partner records support the tagged yeast two-hybrid association with HHATL (Q9HCP6). The positive pair is retained, but an evidence-backed, useful specific binding class or physiological CISD2 mechanism is not established for this interaction. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the AIG1 screen interaction outside the core. Reason: 3 exact source/target/partner records support the tagged yeast two-hybrid association with AIG1 (Q9NVV5-2). The positive pair is retained, but an evidence-backed, useful specific binding class or physiological CISD2 mechanism is not established for this interaction. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the CLN6 screen interaction outside the core. Reason: 3 exact source/target/partner records support the tagged yeast two-hybrid association with CLN6 (Q9NWW5). The positive pair is retained, but an evidence-backed, useful specific binding class or physiological CISD2 mechanism is not established for this interaction. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the PGAP2 screen interaction outside the core. Reason: 3 exact source/target/partner records support the tagged yeast two-hybrid association with PGAP2 (Q9UHJ9-5). The positive pair is retained, but an evidence-backed, useful specific binding class or physiological CISD2 mechanism is not established for this interaction. The Q9UHJ9-5 record includes a 58–307 sufficient region; the source-specific product remains unchanged. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Retain the MAN2B2 screen interaction outside the core. Reason: 3 exact source/target/partner records support the tagged yeast two-hybrid association with MAN2B2 (Q9Y2E5). The positive pair is retained, but an evidence-backed, useful specific binding class or physiological CISD2 mechanism is not established for this interaction. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | KEEP AS NON CORE | Summary: Retain the ACRV1 screen interaction outside the core. Reason: 3 exact source/target/partner records support the tagged yeast two-hybrid association with ACRV1 (P26436). The positive pair is retained, but an evidence-backed, useful specific binding class or physiological CISD2 mechanism is not established for this interaction. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | KEEP AS NON CORE | Summary: Retain the C1orf216 screen interaction outside the core. Reason: 3 exact source/target/partner records support the tagged yeast two-hybrid association with C1orf216 (Q8TAB5). The positive pair is retained, but an evidence-backed, useful specific binding class or physiological CISD2 mechanism is not established for this interaction. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MODIFY | Summary: Specify the verified ATL1 partner class at screening-assay scope. Reason: The exact PMID:32814053 records support a tagged yeast two-hybrid interaction with ATL1 (Q8WXF7), and the authenticated partner is a dynamin-family GTPase. The specific binding class is supported at screening-assay scope; its physiological consequence for CISD2 remains unestablished. ATL1 is a large dynamin-family GTPase; the small-GTPase-binding child is not used. Proposed replacements: GTPase binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | KEEP AS NON CORE | Summary: Retain the SPAG8 screen interaction outside the core. Reason: 3 exact source/target/partner records support the tagged yeast two-hybrid association with SPAG8 (Q99932-2). The positive pair is retained, but an evidence-backed, useful specific binding class or physiological CISD2 mechanism is not established for this interaction. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MODIFY | Summary: Specify the verified STUB1/CHIP partner class at screening-assay scope. Reason: The exact PMID:32814053 records support a tagged yeast two-hybrid interaction with STUB1/CHIP (Q9UNE7), and the authenticated partner is an E3 ubiquitin ligase. The specific binding class is supported at screening-assay scope; its physiological consequence for CISD2 remains unestablished. Proposed replacements: ubiquitin protein ligase binding Supporting Evidence: |
| GO:0005737 cytoplasm | IEA GO_REF:0000117 | ACCEPT | Summary: Cytoplasmic localization includes the ER-associated protein. Reason: The current definition of cytoplasm includes organelles, not only soluble cytosol. Direct human ER localization and the cytosolic CDGSH domain support the broad electronic compartment without implying a freely soluble protein. |
| GO:0005741 mitochondrial outer membrane | IBA GO_REF:0000033 | ACCEPT | Summary: Retain mitochondrial outer-membrane localization with its ortholog scope. Reason: The exact mouse Cisd2 donor Q9CQB5 has direct fractionation evidence from PMID:19451219: endogenous protein is enriched in the outer-membrane fraction, with VDAC and mitoplast/intermembrane-space controls. Human ER localization is also well supported; different relative distributions do not demonstrate loss of the mitochondrial pool. This retains the inherited/ortholog location without presenting the mouse experiment as a human localization assay. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000342619 SUPPORTS TRANSFER Current source identities resolve mouse Cisd2, mouse/rat Cisd1, fly Cisd and human CISD1. The exact mouse Cisd2 outer-membrane IDA supports transfer; the historical PAINT node and alignment were not reconstructed. |
| GO:0005741 mitochondrial outer membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Retain mitochondrial outer-membrane localization with its ortholog scope. Reason: The exact mouse Cisd2 donor Q9CQB5 has direct fractionation evidence from PMID:19451219: endogenous protein is enriched in the outer-membrane fraction, with VDAC and mitoplast/intermembrane-space controls. Human ER localization is also well supported; different relative distributions do not demonstrate loss of the mitochondrial pool. This retains the inherited/ortholog location without presenting the mouse experiment as a human localization assay. |
| GO:0005741 mitochondrial outer membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Retain mitochondrial outer-membrane localization with its ortholog scope. Reason: The exact mouse Cisd2 donor Q9CQB5 has direct fractionation evidence from PMID:19451219: endogenous protein is enriched in the outer-membrane fraction, with VDAC and mitoplast/intermembrane-space controls. Human ER localization is also well supported; different relative distributions do not demonstrate loss of the mitochondrial pool. This retains the inherited/ortholog location without presenting the mouse experiment as a human localization assay. |
| GO:0005783 endoplasmic reticulum | IDA GO_REF:0000052 | ACCEPT | Summary: Retain direct ER localization. Reason: The current HPA record classifies CISD2 as ER-localized with supported ICC/IF reliability. Independent tagged human CISD2 localization and the original NAF-1 study corroborate ER association. The HPA image itself was not reinterpreted here. |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:20010695 Antagonism of Beclin 1-dependent autophagy by BCL-2 at the e... | ACCEPT | Summary: CISD2 is an ER-membrane protein. Reason: Human NAF-1 localization, membrane fractionation and topology experiments support a membrane-anchored protein with a cytosolic CDGSH domain. This is consistent with tagged human ERIS/Miner1 localization and the retained ortholog/electronic evidence. |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000120 | ACCEPT | Summary: CISD2 is an ER-membrane protein. Reason: Human NAF-1 localization, membrane fractionation and topology experiments support a membrane-anchored protein with a cytosolic CDGSH domain. This is consistent with tagged human ERIS/Miner1 localization and the retained ortholog/electronic evidence. |
| GO:0010506 regulation of autophagy | IEA GO_REF:0000002 | MODIFY | Summary: Specify the demonstrated negative regulation of autophagy. Reason: The original H1299 depletion and 4-hour-starvation experiments link NAF-1 to the BCL2–BECN1 complex and show increased Beclin 1-dependent autophagic flux when NAF-1 is reduced. The performed molecular contribution supports a negative regulatory direction, beyond a generic requirement or a mitochondrial-damage phenotype. This does not assert direct inhibition of an autophagy enzyme or universal suppression in every setting. Proposed replacements: negative regulation of autophagy Supporting Evidence: |
| GO:0010506 regulation of autophagy | IMP PMID:20010695 Antagonism of Beclin 1-dependent autophagy by BCL-2 at the e... | MODIFY | Summary: Specify the demonstrated negative regulation of autophagy. Reason: The original H1299 depletion and 4-hour-starvation experiments link NAF-1 to the BCL2–BECN1 complex and show increased Beclin 1-dependent autophagic flux when NAF-1 is reduced. The performed molecular contribution supports a negative regulatory direction, beyond a generic requirement or a mitochondrial-damage phenotype. This does not assert direct inhibition of an autophagy enzyme or universal suppression in every setting. Proposed replacements: negative regulation of autophagy Supporting Evidence: |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | ACCEPT | Summary: Retain the broad membrane compartment. Reason: The original NK-cell membrane-proteome abstract is available, but its exact target table was not recovered. Independent direct human ER-membrane experiments establish the broad location, so the biological annotation is retained without claiming the original mass-spectrometry hit has been independently reconstructed. |
| GO:0032991 protein-containing complex | IDA GO_REF:0000054 | KEEP AS NON CORE | Summary: Retain the broad protein-complex location outside the core. Reason: The exact historical LIFEdb fusion-localization image has not been recovered. Independent human soluble-domain crystallography demonstrates a stable homodimer, and cellular assays identify BCL2-containing complexes, supporting the broad complex annotation. These independent results are not presented as the original LIFEdb experiment. Retain this supported but nonspecific compartment outside the defining molecular core; the source-access gap does not negate the independent complex evidence. |
| GO:0042803 protein homodimerization activity | IDA PMID:19580816 Crystal structure of Miner1: The redox-active 2Fe-2S protein... | ACCEPT | Summary: Retain the directly observed CISD2 homodimer. Reason: The source resolves a tightly packed parallel dimer of recombinant human residues 57–135 carrying C92S, with strand-swapped beta sheets. The construct omits the membrane anchor and does not alone establish every membrane-context assembly, but directly supports the homodimerization capacity. Supporting Evidence: PMID:19580816 parallel homodimeric structure |
| GO:0051537 2 iron, 2 sulfur cluster binding | IBA GO_REF:0000033 | ACCEPT | Summary: CISD2 coordinates a [2Fe-2S] cluster in each protomer. Reason: Human soluble-domain spectroscopy and crystallography directly resolve the clusters and their unusual three-cysteine/one-histidine coordination. The structure uses residues 57–135 with C92S to improve preparation stability. This supports the cluster-binding assertion without interpreting a measured redox potential as a demonstrated electron-transfer enzyme reaction. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000342619 SUPPORTS TRANSFER The target itself has direct structural and biochemical cluster evidence, appropriately contributing descendant support to the PAINT assertion. Official donor identities/current records are authenticated; historical node placement was not reconstructed. |
| GO:0051537 2 iron, 2 sulfur cluster binding | IDA PMID:19580816 Crystal structure of Miner1: The redox-active 2Fe-2S protein... | ACCEPT | Summary: CISD2 coordinates a [2Fe-2S] cluster in each protomer. Reason: Human soluble-domain spectroscopy and crystallography directly resolve the clusters and their unusual three-cysteine/one-histidine coordination. The structure uses residues 57–135 with C92S to improve preparation stability. This supports the cluster-binding assertion without interpreting a measured redox potential as a demonstrated electron-transfer enzyme reaction. |
| GO:0051537 2 iron, 2 sulfur cluster binding | IEA GO_REF:0000120 | ACCEPT | Summary: CISD2 coordinates a [2Fe-2S] cluster in each protomer. Reason: Human soluble-domain spectroscopy and crystallography directly resolve the clusters and their unusual three-cysteine/one-histidine coordination. The structure uses residues 57–135 with C92S to improve preparation stability. This supports the cluster-binding assertion without interpreting a measured redox potential as a demonstrated electron-transfer enzyme reaction. |
| GO:0097038 perinuclear endoplasmic reticulum | IDA PMID:17376863 MitoNEET is an iron-containing outer mitochondrial membrane ... | ACCEPT | Summary: Retain direct perinuclear ER localization of human Miner1. Reason: The original source tests human Miner1 constructs independently of its more extensive mitoNEET experiments. C-terminal V5-tagged human Miner1 in COS7 cells has a strong perinuclear and reticular ER pattern. The paper's mitochondrial membrane extraction experiments on mitoNEET are not transferred to CISD2. Supporting Evidence: |
| GO:0140132 iron-sulfur cluster chaperone activity | IDA PMID:23717386 Nutrient-deprivation autophagy factor-1 (NAF-1): biochemical... | NEW | Summary: CISD2 directly delivers its iron–sulfur cluster to an apo-acceptor. Reason: Purified NAF-1 residues 57–135 transfer a bound [2Fe-2S] cluster to apo-ferredoxin, monitored by spectrophotometry and native gels; oxidation state, acceptor thiols and the H114 ligand affect delivery. This directly matches cluster chaperone activity. The cellular iron-sensor experiment reports mitochondrial labile iron delivery, not intact-cluster transfer to an identified physiological acceptor. The term is not an is_a ancestor or descendant of the existing cluster-binding term; no additional process or transferase activity is proposed. Supporting Evidence: PMID:23717386 transfer its 2Fe-2S cluster to an apo-acceptor protein |
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Download this section (compressed HTML)Q: Which physiological apo-protein accepts a CISD2 cluster in human cells, and how is intact-cluster delivery distinguished from release and subsequent iron uptake?
Q: How do BCL2 binding, cluster occupancy and membrane-contact context determine CISD2 effects on ER–mitochondrial calcium handling?
Q: Which screen-detected CISD2 interactions occur endogenously, and which physiological consequence follows from the verified partner-class associations?
Experiment: Trace an isotopically labeled CISD2 cluster into candidate endogenous acceptors under controlled redox conditions, combining acceptor-specific spectroscopy with CISD2 ligand-mutant and iron-release controls.
Experiment: Compare endogenous and matched-expression CISD2–BCL2 perturbations with simultaneous ER and mitochondrial calcium measurements, membrane-contact quantification and Beclin-dependent autophagic flux.
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