DCT-1 (DAF-16/FOXO controlled germline tumor affecting-1; ceBNIP3) is the single C. elegans member of the BNIP3/NIX (NIP3) family. It is a tail-anchored, single-pass protein of the mitochondrial outer membrane (OMM), expressed in all somatic tissues from embryo to adult, and acts as the main receptor-type mediator of stress-induced mitophagy in the worm. DCT-1 carries a WXXL LIR-like motif and colocalizes with the Atg8/LC3 homolog LGG-1 on mitochondria, consistent with tethering damaged mitochondria to forming autophagosomes as mammalian NIX/BNIP3 do; direct DCT-1–LGG-1 binding has not been shown. DCT-1 acts in a common genetic pathway with PINK-1 and PDR-1/Parkin: under oxidative stress it is ubiquitinated at Lys-26 in a PINK-1-dependent manner, and the protection conferred by DCT-1 overexpression requires PINK-1 and PDR-1. dct-1 is a direct DAF-16/FOXO target and is induced by SKN-1/Nrf2, linking mitophagy to mitochondrial biogenesis in a homeostatic feedback loop. Loss of dct-1 causes accumulation of dysfunctional mitochondria (increased mass, depolarization, reduced ATP, elevated ROS and cytosolic Ca2+) and suppresses the extended lifespan of daf-2, isp-1 and clk-1 mutants. DCT-1 also self-associates through its transmembrane domain. When overexpressed in mammalian cells it binds CED-9 and the CED-3 prodomain and kills cells by a BH3- and caspase-independent mechanism; a physiological role in C. elegans apoptosis has not been demonstrated.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005741 mitochondrial outer membrane | IBA GO_REF:0000033 | ACCEPT | Summary: IBA for mitochondrial outer membrane from PAINT node PTN001032684 (Eumetazoa), seeded by fly BNIP3, human BNIP3/NIX and worm DCT-1 itself. DCT-1 has its own IDA support for OMM localization (PMID:25896323), so the worm gene is one of the experimental descendants grounding the node. Reason: OMM is the site of DCT-1 mitophagy-receptor activity. The inheritance claim is sound: OMM targeting via the C-terminal transmembrane anchor is conserved across the whole family, and DCT-1 has direct experimental support. Supporting Evidence: file:worm/dct-1/dct-1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion outer membrane PMID:11114722 Like BNIP3, the TM domain of ceBNIP3 mediates the localization of the protein to mitochondria file:worm/dct-1/dct-1-deep-research-falcon.md DCT-1 is an integral OMM protein |
| GO:0000423 mitophagy | IBA GO_REF:0000033 | ACCEPT | Summary: IBA for mitophagy from PAINT node PTN001032684, seeded by fly BNIP3, human BNIP3 and worm DCT-1. DCT-1 itself has an IMP for mitophagy from Palikaras et al. 2015 (PMID:25896323), so its appearance in the WITH list reflects experimental grounding on the target, not circularity. Reason: Mitophagy is the core, conserved process of the BNIP3/NIX family and is directly demonstrated for DCT-1 in vivo. The IBA adds that the function is inherited rather than nematode-specific, which is consistent with fly and mammalian data. Supporting Evidence: PMID:25896323 We find that DCT-1 is a key mediator of mitophagy and longevity assurance under conditions of stress in C. elegans |
| GO:0043065 positive regulation of apoptotic process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA for positive regulation of apoptotic process from PAINT node PTN001032684. All seeds are vertebrate (human BNIP3/NIX, mouse Bnip3l, rat Bnip3/Bnip3l, zebrafish). For DCT-1 the only supporting data are heterologous: in transfected mammalian cells ceBNIP3 cooperates with CED-3 to promote apoptosis (PMID:9824163) and kills cells by a BH3- and caspase-independent mechanism (PMID:11114722). No study has shown that dct-1 loss or gain alters developmental or germline apoptosis in the worm. Reason: The conserved pro-death capacity of BNIP3-family proteins is retained by DCT-1 when expressed in mammalian cells, which is consistent with the node placement, and WormBase curators annotated apoptotic process (IMP) from the same work. This is kept as non-core rather than removed: the inference is plausible, but the physiological worm role is mitophagy and the C. elegans core apoptosis pathway (EGL-1/CED-9/CED-4/CED-3) has not been shown to require DCT-1. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: CONTEXT OR TISSUE MISMATCH Sources checked: PANTHER:PTN001032684 SUPPORTS TRANSFER Eumetazoan node; pro-apoptotic statements seeded only by vertebrate BNIP3/NIX experimental annotations. Retained pro-death activity of ceBNIP3 in mammalian cells is consistent with inheritance of the capacity, though not with an in vivo worm role. UniProtKB:Q12983 · BNIP3 SUPPORTS SOURCE BUT NOT TARGET Human BNIP3 pro-death data are robust in mammalian cells; no equivalent worm in vivo data. UniProtKB:O60238 · BNIP3L SUPPORTS SOURCE BUT NOT TARGET NIX pro-apoptotic activity is context-dependent and overexpression-driven. Supporting Evidence: PMID:9824163 Transfection of ceBNIP3 and CED-3 results in enhanced proteolytic processing of the CED-3 zymogen and in cooperative induction of apoptosis PMID:11114722 ceBNIP3 kills mammalian cells by a caspase-independent mechanism |
| GO:0043653 mitochondrial fragmentation involved in apoptotic process | IBA GO_REF:0000033 | REMOVE | Summary: IBA for mitochondrial fragmentation involved in apoptotic process, placed at the eumetazoan node PTN001032684 on the basis of a single seed, human BNIP3. There is no evidence that DCT-1 drives mitochondrial fragmentation during apoptosis in C. elegans. The only worm data on mitochondrial morphology run the other way: loss of dct-1 produces fragmented and disorganized mitochondrial networks because damaged mitochondria are not cleared. Reason: A specialized mammalian apoptotic mechanism attested by one vertebrate paralog has been placed at a node spanning nematodes and insects. DCT-1 kills mammalian cells by a BH3- and caspase-independent mechanism, no in vivo apoptotic role for DCT-1 has been shown, and mitochondrial fragmentation is not an established step of nematode apoptosis that DCT-1 performs. The transfer to worm is not supported. Propagation Review Root cause: PROPAGATION BAD Failure modes: LINEAGE OR TAXON MISMATCH FUNCTIONAL DIVERGENCE Sources checked: PANTHER:PTN001032684 SUPPORTS SOURCE BUT NOT TARGET Node placed at Eumetazoa (taxon:6072) although the sole experimental seed is human BNIP3; no invertebrate member has supporting data. UniProtKB:Q12983 · BNIP3 SUPPORTS SOURCE BUT NOT TARGET Human BNIP3 IDA (mammalian cells) supports the term for BNIP3; the apoptotic fragmentation mechanism has not been tested for any invertebrate ortholog. UniProtKB:Q09969 · dct-1 NOT RELEVANT Target. Loss of dct-1 produces fragmented networks through failed mitophagy, which is the opposite relationship to the one the term asserts. Supporting Evidence: PMID:11114722 although ceBNIP3 interacts with CED-9 and CED-3 it kills by a BH3- and caspase-independent mechanism file:worm/dct-1/dct-1-uniprot.txt accumulation of defective mitochondria that have increased mass, altered network morphology |
| GO:0005634 nucleus | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: IBA asserting that DCT-1 is active in the nucleus, from PAINT node PTN001032684, seeded by rat Bnip3 and human BNIP3/NIX. There is no experimental evidence for nuclear DCT-1 in C. elegans; all worm data place it on the mitochondrial outer membrane. The mammalian nuclear pools (e.g. nuclear BNIP3 in glioma cells) are cell-type specific and no nuclear activity is defined for the family. Reason: is_active_in nucleus claims a site of activity that is not established for any invertebrate member and is not the site of the conserved mitophagy-receptor function. The vertebrate nuclear observations reflect specific cellular contexts rather than an ancestral property. The parallel human BNIP3L review marks the same IBA as over-annotated. Propagation Review Root cause: PROPAGATION BAD Failure modes: CONTEXT OR TISSUE MISMATCH LINEAGE OR TAXON MISMATCH Sources checked: PANTHER:PTN001032684 SUPPORTS SOURCE BUT NOT TARGET Eumetazoan node; nucleus seeds are vertebrate only. UniProtKB:Q12983 · BNIP3 SUPPORTS SOURCE BUT NOT TARGET Nuclear BNIP3 is reported in specific mammalian cell contexts. UniProtKB:O60238 · BNIP3L SOURCE WEAK OR INFERRED NIX data describe nuclear envelope localization of a tail-anchored protein rather than nucleoplasmic activity. RGD:620800 · Bnip3 (rat) SUPPORTS SOURCE BUT NOT TARGET Rat Bnip3 nuclear observation is context-specific. Supporting Evidence: file:worm/dct-1/dct-1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion outer membrane |
| GO:0005739 mitochondrion | IEA GO_REF:0000117 | ACCEPT | Summary: IEA (ARBA) for mitochondrion. Correct but general; DCT-1 is an OMM protein. Reason: Correct general localization, consistent with the experimentally supported OMM localization. Supporting Evidence: PMID:11114722 the TM domain of ceBNIP3 mediates the localization of the protein to mitochondria |
| GO:0005740 mitochondrial envelope | IEA GO_REF:0000002 | ACCEPT | Summary: IEA from the InterPro BNIP3 family entry (IPR010548). DCT-1 is in the outer membrane, part of the mitochondrial envelope. Reason: Correct, if less specific than mitochondrial outer membrane, which is separately annotated with experimental evidence. Supporting Evidence: PMID:11114722 the TM domain of ceBNIP3 mediates the localization of the protein to mitochondria |
| GO:0005741 mitochondrial outer membrane | IEA GO_REF:0000044 | ACCEPT | Summary: IEA from the UniProt subcellular location mapping (Mitochondrion outer membrane, supported in UniProt by PMID:25896323). Reason: Correct core localization, redundant with the IDA annotation from PMID:25896323. Supporting Evidence: file:worm/dct-1/dct-1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion outer membrane |
| GO:0016020 membrane | IEA GO_REF:0000002 | ACCEPT | Summary: IEA from InterPro mapping. DCT-1 is a single-pass membrane protein. Reason: Correct but very broad; the specific OMM localization is annotated separately. Supporting Evidence: PMID:11114722 ceBNIP3 contains a C-terminal transmembrane (TM) domain |
| GO:0042802 identical protein binding | IEA GO_REF:0000117 | MODIFY | Summary: IEA (ARBA) for identical protein binding. DCT-1 self-associates through its TM domain and is detected as a 50 kDa homodimer. Reason: The self-association is real but the more specific protein homodimerization activity (GO:0042803) is supported directly by PMID:11114722 and better describes it. Proposed replacements: protein homodimerization activity Supporting Evidence: PMID:11114722 ceBNIP3 is expressed primarily as a 25 kDa monomer and a 50 kDa homodimer |
| GO:0043065 positive regulation of apoptotic process | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: IEA from InterPro2GO on the BNIP3 family entry. DCT-1 promotes cell death when overexpressed in mammalian cells, but no physiological apoptotic role has been shown in the worm. Reason: Same assessment as the IBA for this term: a retained, family-wide pro-death capacity seen in heterologous expression, secondary to the physiological mitophagy function. Supporting Evidence: PMID:9824163 ceBNIP3 may be a novel component of the C. elegans apoptosis paradigm and may initiate apoptosis by recruiting CED-3 to mitochondria and other cytoplasmic membranes |
| GO:0000423 mitophagy | IMP PMID:25896323 Coordination of mitophagy and mitochondrial biogenesis durin... | ACCEPT | Summary: IMP from Palikaras et al. 2015. dct-1 knockdown or deletion blocks stress-induced mitophagy and causes accumulation of damaged mitochondria; DCT-1 acts with PINK-1 and PDR-1. Reason: Core process, directly demonstrated in vivo in C. elegans. Supporting Evidence: PMID:25896323 We find that DCT-1 is a key mediator of mitophagy and longevity assurance under conditions of stress in C. elegans. Impairment of mitophagy compromises stress resistance file:worm/dct-1/dct-1-uniprot.txt Required for the induction of mitophagy under stress conditions |
| GO:0051726 regulation of cell cycle | IGI PMID:17934462 DAF-16/FOXO targets genes that regulate tumor growth in Caen... | KEEP AS NON CORE | Summary: IGI from Pinkston-Gosse & Kenyon 2007, a screen of DAF-16 targets for effects on germline tumor growth (gld-1 tumor background; with UniProtKB:O16850). dct-1 RNAi affected tumor cell proliferation. Reason: Curator annotation from a genetic screen whose full text is not cached. The tumor-growth phenotype is most likely an indirect consequence of altered mitochondrial quality control rather than a direct cell-cycle regulatory activity, so it is retained as non-core. Supporting Evidence: PMID:17934462 Twenty-nine of 734 genes tested influenced germline-tumor cell proliferation or p53-dependent apoptosis |
| GO:0005741 mitochondrial outer membrane | IDA PMID:25896323 Coordination of mitophagy and mitochondrial biogenesis durin... | ACCEPT | Summary: IDA from Palikaras et al. 2015: DCT-1::GFP colocalizes with mitochondrial markers and is accessible to proteinase K in isolated mitochondria, whereas matrix HSP-60 is protected. Reason: Core localization with direct experimental evidence; the site of mitophagy-receptor function. Supporting Evidence: file:worm/dct-1/dct-1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion outer membrane file:worm/dct-1/dct-1-deep-research-falcon.md In vivo imaging and protease protection assays show DCT-1::GFP co-localizes with mitochondrial markers and is proteinase K–accessible, consistent with OMM exposure |
| GO:0002020 protease binding | IPI PMID:11114722 The C. elegans orthologue ceBNIP3 interacts with CED-9 and C... | KEEP AS NON CORE | Summary: IPI with CED-3 caspase (P42573), from co-expression in heterologous cells. Reason: The CED-3 interaction is experimentally reported in two independent studies and is retained. It was observed on overexpression outside the worm, co-expression with CED-3 did not enhance killing in this study, and no in vivo consequence is known, so it is not a core function. Supporting Evidence: PMID:11114722 ceBNIP3 interacts with CED-3 but co-expression of CED-3 and ceBNIP3 does not significantly enhance induction of cell death in the presence or absence of CED-4 |
| GO:0002020 protease binding | IPI PMID:9824163 Regulation of apoptosis by a Caenorhabditis elegans BNIP3 ho... | KEEP AS NON CORE | Summary: IPI with the CED-3 zymogen (P42573) via its prodomain, in transfected mammalian cells (Yasuda et al. 1998). Reason: Direct binding to the proCED-3 prodomain is reported, which makes this more specific than protein binding. The interaction is heterologous and has no demonstrated role in worm apoptosis, so it is non-core. Supporting Evidence: PMID:9824163 CeBNIP3 also efficiently heterodimerizes with the cell death protease proCED-3 by direct binding via the prodomain |
| GO:0005515 protein binding | IPI PMID:11114722 The C. elegans orthologue ceBNIP3 interacts with CED-9 and C... | REMOVE | Summary: IPI with CED-9 (P41958). The interaction is mediated by the ceBNIP3 TM domain, not its BH3-like domain. Reason: Bare protein binding conveys no functional information. The paper shows the BH3-like domain does not mediate the CED-9 interaction, so BH3 domain binding would be wrong, and no other informative MF is supported. Removal does not mean the interaction is false. Supporting Evidence: PMID:11114722 ceBNIP3 protein interacts with CED-9 and BCL-XL, but unlike other pro-apoptotic BCL-2 family members, the BH3-like domain does not participate in dimerization. The ceBNIP3 TM domain mediates interaction with both CED-9 and BCL-XL |
| GO:0005515 protein binding | IPI PMID:9824163 Regulation of apoptosis by a Caenorhabditis elegans BNIP3 ho... | REMOVE | Summary: IPI with CED-9 (P41958) in transfected mammalian cells (Yasuda et al. 1998). Reason: Bare protein binding is uninformative and no more specific MF is supported for the CED-9 interaction. Removal does not mean the interaction is false; the complex is captured by the protein-containing complex annotation from the same paper. Supporting Evidence: PMID:9824163 In transiently transfected mammalian cells, ceBNIP3 complexes with CED-9, the worm homolog of BCL-2 |
| GO:0006915 apoptotic process | IMP PMID:11114722 The C. elegans orthologue ceBNIP3 interacts with CED-9 and C... | KEEP AS NON CORE | Summary: IMP from Cizeau et al. 2000, based on ceBNIP3 overexpression and domain-deletion mutants killing mammalian cells. The death was BH3- and caspase-independent. Reason: Curator annotation retained. The evidence is heterologous overexpression and the death mechanism is caspase-independent, so this is not evidence of a physiological role in worm apoptosis; mitophagy is the core function. Supporting Evidence: PMID:11114722 Like BNIP3, the TM domain of ceBNIP3 mediates the localization of the protein to mitochondria and is also necessary for homodimerization and cell death in mammalian cells |
| GO:0008340 determination of adult lifespan | IMP PMID:16380712 Identification of direct DAF-16 targets controlling longevit... | KEEP AS NON CORE | Summary: IMP from Oh et al. 2006 (direct DAF-16 targets identified by ChIP; RNAi of targets altered lifespan). Palikaras et al. 2015 independently showed that dct-1 knockdown suppresses the extended lifespan of daf-2, isp-1 and clk-1 mutants. Reason: Lifespan is a downstream organismal consequence of DCT-1-dependent mitochondrial quality control rather than a core process. Supporting Evidence: PMID:16380712 inactivation of more than half of these genes significantly altered DAF-16-dependent functions, including life span, fat storage and dauer formation file:worm/dct-1/dct-1-uniprot.txt RNAi-mediated knockdown in daf-2, isp-1, or clk-1 mutant backgrounds suppresses their increased lifespan phenotype |
| GO:0031966 mitochondrial membrane | IDA PMID:11114722 The C. elegans orthologue ceBNIP3 interacts with CED-9 and C... | ACCEPT | Summary: IDA for mitochondrial membrane localization of ceBNIP3, mediated by its TM domain (Cizeau et al. 2000). Reason: Correct; the outer membrane is resolved by later work (PMID:25896323) and annotated separately. Supporting Evidence: PMID:11114722 the TM domain of ceBNIP3 mediates the localization of the protein to mitochondria |
| GO:0042803 protein homodimerization activity | IDA PMID:11114722 The C. elegans orthologue ceBNIP3 interacts with CED-9 and C... | ACCEPT | Summary: IDA for homodimerization; ceBNIP3 is detected as a 50 kDa homodimer, and the TM domain is required. Reason: Directly demonstrated, TM-domain-mediated self-association, a conserved structural property of the BNIP3 family. Supporting Evidence: PMID:11114722 ceBNIP3 is expressed primarily as a 25 kDa monomer and a 50 kDa homodimer |
| GO:0005515 protein binding | IPI PMID:9824163 Regulation of apoptosis by a Caenorhabditis elegans BNIP3 ho... | REMOVE | Summary: WormBase IPI with CED-3 (WB:WBGene00000417, ced-3) in transfected mammalian cells. The same interaction is already annotated as protease binding (GO:0002020) from this paper. Reason: Bare protein binding adds nothing; the informative form of this interaction (protease binding with CED-3) is already present. Removal does not mean the interaction is false. Supporting Evidence: PMID:9824163 CeBNIP3 also efficiently heterodimerizes with the cell death protease proCED-3 by direct binding via the prodomain |
| GO:0005515 protein binding | IPI PMID:9824163 Regulation of apoptosis by a Caenorhabditis elegans BNIP3 ho... | REMOVE | Summary: WormBase IPI with CED-9 (WB:WBGene00000423, ced-9) in transfected mammalian cells; duplicates the UniProt CED-9 row from this paper. Reason: Bare protein binding is uninformative and no more specific MF is supported for the CED-9 interaction. Removal does not mean the interaction is false. Supporting Evidence: PMID:9824163 In transiently transfected mammalian cells, ceBNIP3 complexes with CED-9, the worm homolog of BCL-2 |
| GO:0032991 protein-containing complex | IPI PMID:9824163 Regulation of apoptosis by a Caenorhabditis elegans BNIP3 ho... | KEEP AS NON CORE | Summary: IPI for a ternary ceBNIP3–CED-9–CED-3 complex formed on co-expression in mammalian cells. Reason: The complex is experimentally reported but only on overexpression in a heterologous system, and it has no defined in vivo role. The generic term is retained as a non-core record of that observation. Supporting Evidence: PMID:9824163 In cells coexpressing CED-9, ceBNIP3 and CED-3, all three proteins exist as a ternary complex |
| GO:0140580 mitochondrion autophagosome adaptor activity | ISS PMID:25896323 Coordination of mitophagy and mitochondrial biogenesis durin... | NEW | Summary: Proposed MF. DCT-1 is the worm ortholog of the mammalian mitophagy receptors NIX/BNIP3, which bind LC3/GABARAP through a LIR and tether mitochondria to autophagosomes. DCT-1 is an OMM protein required for stress-induced mitophagy, carries a WXXL LIR-like motif, and colocalizes with LGG-1 on mitochondria. Reason: The activity is inferred by orthology together with worm data: localization, a conserved LIR-like motif, LGG-1 colocalization, and an in vivo mitophagy requirement. Direct DCT-1–LGG-1 binding and LIR dependence have not been shown in the worm, so the evidence is coded ISS rather than IDA. PAINT currently places GO:0140580 at a Euteleostomi node (PTN002689498) seeded by human BNIP3 alone, which reflects the absence of invertebrate binding data rather than evidence against the activity. The core-function claim should be upgraded if a LIR-mutant or binding experiment is done. Supporting Evidence: file:worm/dct-1/dct-1-deep-research-falcon.md It colocalizes with LGG-1/Atg8 and facilitates recruitment of the autophagy machinery to mitochondria, engaging receptor-mediated mitophagy similar to mammalian BNIP3/NIX PMID:25896323 We find that DCT-1 is a key mediator of mitophagy and longevity assurance under conditions of stress in C. elegans |
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Download this section (compressed HTML)Q: Does DCT-1 bind LGG-1 and/or LGG-2 directly, and is the WXXL motif the binding site?
Q: Does DCT-1 contribute to developmental or germline apoptosis in vivo, or is its pro-death activity seen only on overexpression in mammalian cells?
Q: Should the PAINT statement for mitochondrial fragmentation involved in apoptotic process (GO:0043653), seeded only by human BNIP3, sit at the eumetazoan node PTN001032684 or at a vertebrate node?
Q: Which E3 ligase ubiquitinates DCT-1 at Lys-26, and does ubiquitination promote LGG-1 recruitment?
Experiment: In vitro binding (GST-LGG-1 pulldown or ITC with the DCT-1 LIR peptide) and in vivo co-immunoprecipitation from stressed worms, comparing wild type with a WXXL→AXXA CRISPR allele.
Hypothesis: DCT-1 binds LGG-1 directly via its WXXL LIR-like motif
Experiment: Measure mitophagy (mtRosella or mt-Keima) in a dct-1 LIR-mutant knock-in versus wild type and a dct-1 null under paraquat stress.
Hypothesis: The LIR-like motif is required for DCT-1-mediated mitophagy
Experiment: Count embryonic and germline (basal and DNA-damage-induced) cell corpses in dct-1 null mutants, alone and in sensitized ced-3(partial) or ced-9(gf) backgrounds.
Hypothesis: DCT-1 is not required for physiological apoptosis
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