BNIP3L (NIX) is a tail-anchored, atypical BH3-containing member of the BNIP3/NIP3 family that is inserted into the mitochondrial outer membrane via its C-terminal transmembrane helix, with its N-terminal disordered region facing the cytosol. Its principal, conserved function is as a selective autophagy (mitophagy) receptor: an LC3-interacting region in the cytosolic domain binds Atg8-family proteins (LC3 and GABARAP/GABARAPL1/GABARAPL2), tethering mitochondria to the forming autophagosome and driving their programmed autophagic clearance. This is most prominent during terminal erythroid/reticulocyte maturation and other developmentally programmed or stress-induced episodes of mitochondrial turnover. NIX also participates in non-canonical mitochondrial quality control through ROS-dependent interaction with SPATA18/MIEAP, and under hypoxia it is induced by HIF and promotes pro-survival macroautophagy via its atypical BH3 domain. Although first described as a pro-apoptotic BCL-2-family protein, its effects on cell death are context-dependent and direction-dependent (it can both promote and inhibit cell death) and act largely through mitochondrial membrane permeability/necrosis rather than classical cytochrome-c/caspase apoptosis. Beyond mitochondria, NIX can independently localize to peroxisomes and act as a selective autophagy receptor for their clearance (pexophagy), broadening its cargo selectivity. NIX abundance is held in check by constitutive ubiquitin-mediated turnover: an SCF(FBXL4) ubiquitin ligase complex at the mitochondrial outer membrane, with the phosphatase PPTC7 as a cofactor, degrades NIX (and BNIP3) to restrain basal mitophagy, while hypoxia/HIF signaling induces NIX transcription. NIX is also exploited by several viruses, which hijack NIX-mediated mitophagy to degrade mitochondrial antiviral signaling components.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0043065 positive regulation of apoptotic process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: NIX/BNIP3L was first characterized as a pro-apoptotic BCL-2/NIP3-family protein and can promote cell death in some contexts, but this is direction-dependent and atypical (necrosis/membrane permeability rather than classical caspase apoptosis). Reason: The pro-apoptotic role is genuine but secondary and context-dependent relative to the conserved mitophagy-receptor function; the same gene also has negative-regulation-of-apoptosis annotations, underscoring that cell-death regulation is contextual. Supporting Evidence: PMID:9973195 Overexpression of BNIP3alpha in transfected cells results in apoptosis and suppresses the antiapoptosis activity of E1B-19K and BCL-xL. PMID:21264228 in contrast to other mitochondrial Bcl-2 family proteins, NIX and BNIP3 are not involved in the release of cytochrome c and the resulting caspase-dependent apoptosis, but rather related to necrosis through the regulation of mitochondrial permeability transition pore (MPTP) |
| GO:0043653 mitochondrial fragmentation involved in apoptotic process | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Mitochondrial fragmentation involved in apoptotic process IBA from PTN001032684, seeded only by the paralog BNIP3. Reason: The only experimental seed for this node assertion is BNIP3. There is no experimental evidence that NIX drives apoptotic mitochondrial fragmentation; NIX-dependent mitochondrial clearance proceeds independently of the apoptotic machinery, and NIX is not involved in cytochrome c release. This matches the mouse Bnip3l review and the PTHR15186 family review, which treat the term as at most a vertebrate BNIP3 property. Supporting Evidence: PMID:18048346 Mitochondrial clearance does not require BAX, BAK, BCL-X(L), BIM, or PUMA, indicating that NIX does not function through established proapoptotic pathways. PMID:21264228 in contrast to other mitochondrial Bcl-2 family proteins, NIX and BNIP3 are not involved in the release of cytochrome c and the resulting caspase-dependent apoptosis, but rather related to necrosis through the regulation of mitochondrial permeability transition pore (MPTP) |
| GO:0005783 endoplasmic reticulum | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: ER localization is reported for NIX (it was detected in nuclear envelope, ER and mitochondria, and linked to ER Ca2+ handling), but it is a secondary site relative to the mitochondrial outer membrane where the mitophagy-receptor function operates. Reason: ER localization is documented but is not the primary functional compartment. ORGANELLES check (2026-11-04, ER batch 1). The PAINT IBD at PTN000795991 (PTHR15186) is seeded by BNIP3L itself (O60238, IDA PMID:10381623) and its paralog BNIP3 (Q12983), both of which have direct ER evidence, so the node placement is sound and the target among its own seeds is expected. The ER claim holds: human B5/NIX was seen in the nuclear envelope, ER and mitochondria (PMID:10381623, abstract only), and endogenous cardiac NIX localizes to the mitochondria and the ER/SR in mouse (PMID:19065046). On the is_active_in qualifier, which is not changed: the review does show an activity of the ER pool, since ER/SR-targeted NIX sets ER/SR Ca2+ stores and drives cell death through ER-to-mitochondria crosstalk (PMID:19065046, mouse), so is_active_in is defensible for that secondary role; it does not apply to the mitophagy-receptor function, which operates at the mitochondrial outer membrane. Hence KEEP_AS_NON_CORE, consistent with the IEA and IDA ER rows. Supporting Evidence: PMID:10381623 localizes in nuclear envelope, endoplasmic reticulum and mitochondria PMID:21264228 NIX was also shown to localize to endoplasmic reticulum (ER) and increase the store of Ca++, leading to Ca++ influx into mitochondria and cell death PMID:19065046 Endogenous cardiac NIX and recombinant NIX localize both to the mitochondria and to the ER/SR. PMID:19065046 Nix mutants specific to ER/SR or mitochondria activated caspases and were equally lethal, but only ER/SR-Nix caused loss of the mitochondrial membrane potential. |
| GO:0005741 mitochondrial outer membrane | IBA GO_REF:0000033 | ACCEPT | Summary: The mitochondrial outer membrane is the core functional location of NIX, where its C-terminal transmembrane anchor inserts and its cytosolic LIR engages the autophagy machinery. Reason: This is the principal functional compartment for the mitophagy-receptor activity and is strongly supported by multiple independent studies. Supporting Evidence: PMID:20200478 Nix is a mitochondrial outer membrane protein that is required for mitochondrial clearance during erythrocyte maturation. PMID:21264228 A mitochondrial outer membrane protein NIX interacted with Mieap in a ROS-dependent manner via the BH3 domain of NIX and the coiled-coil domain of Mieap. |
| GO:0005634 nucleus | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: A nuclear/nuclear-envelope localization derives from the original B5 study; it is weakly supported and is not the functional compartment for the mitophagy-receptor role. Reason: is_active_in nucleus is not supported by a defined nuclear function; the only relevant primary data describe nuclear envelope localization, likely reflecting tail-anchored membrane behavior, not nucleoplasmic activity. Propagation Review Root cause: PROPAGATION BAD Failure modes: CONTEXT OR TISSUE MISMATCH COMPARTMENT OR COMPLEX MISMATCH Sources checked: PANTHER:PTN001032684 SUPPORTS SOURCE BUT NOT TARGET Eumetazoan node; nucleus seeds are rat Bnip3, human BNIP3 and NIX itself. UniProtKB:O60238 · BNIP3L SOURCE WEAK OR INFERRED The target's own seed evidence (PMID:10381623) describes nuclear envelope membrane localization, not nucleoplasmic activity. UniProtKB:Q12983 · BNIP3 SUPPORTS SOURCE BUT NOT TARGET Nuclear BNIP3 is reported in specific cell contexts (e.g. glioma) and is not documented for NIX. RGD:620800 · Bnip3 (rat) SUPPORTS SOURCE BUT NOT TARGET Rat Bnip3 nuclear observation is paralog- and context-specific. Supporting Evidence: PMID:10381623 localizes in nuclear envelope, endoplasmic reticulum and mitochondria |
| GO:0005635 nuclear envelope | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Nuclear envelope localization is reported in the original B5 study (with associated lamin binding), but it is a secondary, weakly characterized site rather than the functional mitophagy compartment. Reason: Nuclear envelope localization is documented experimentally but is not where the conserved mitophagy-receptor function acts; retained as non-core. Supporting Evidence: PMID:10381623 localizes in nuclear envelope, endoplasmic reticulum and mitochondria |
| GO:0005635 nuclear envelope | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Automated subcellular-location transfer of nuclear envelope localization, consistent with the experimental B5 data. Reason: Consistent with documented nuclear envelope localization but secondary to the mitochondrial outer membrane function. Supporting Evidence: PMID:10381623 localizes in nuclear envelope, endoplasmic reticulum and mitochondria |
| GO:0005740 mitochondrial envelope | IEA GO_REF:0000002 | MODIFY | Summary: Mitochondrial envelope is a less specific parent of the mitochondrial outer membrane, where NIX is actually anchored. Reason: The more precise and well-supported localization is the mitochondrial outer membrane; replace the broader envelope term. Proposed replacements: mitochondrial outer membrane Supporting Evidence: PMID:20200478 Nix is a mitochondrial outer membrane protein that is required for mitochondrial clearance during erythrocyte maturation. |
| GO:0005741 mitochondrial outer membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Automated location transfer of the well-supported mitochondrial outer membrane localization. Reason: Strongly supported as the core functional compartment. Supporting Evidence: PMID:20200478 Nix is a mitochondrial outer membrane protein that is required for mitochondrial clearance during erythrocyte maturation. |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Automated transfer of ER localization, consistent with experimental detection of NIX in the ER. Reason: ER localization is documented but is a secondary site relative to the mitochondrial outer membrane. ORGANELLES check (2026-11-04, ER batch 1). The row maps UniProt SL-0095; the UniProt line "Endoplasmic reticulum" carries no evidence tag but rests on the curated subcellular-location reference PMID:10381623 (B5 = NIX), and is corroborated by endogenous NIX at the ER/SR in mouse heart (PMID:19065046). The organelle claim holds; KEEP_AS_NON_CORE as for the IBA and IDA ER rows. Supporting Evidence: PMID:10381623 localizes in nuclear envelope, endoplasmic reticulum and mitochondria file:human/BNIP3L/BNIP3L-uniprot.txt Nucleus envelope. Endoplasmic reticulum. PMID:19065046 Endogenous cardiac NIX and recombinant NIX localize both to the mitochondria and to the ER/SR. |
| GO:0016020 membrane | IEA GO_REF:0000120 | MARK AS OVER ANNOTATED | Summary: NIX is a single-pass tail-anchored membrane protein, so generic membrane localization is correct but uninformative. Reason: The generic membrane term is subsumed by the specific and well-supported mitochondrial outer membrane localization. Supporting Evidence: file:human/BNIP3L/BNIP3L-uniprot.txt Single-pass |
| GO:0043065 positive regulation of apoptotic process | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Automated transfer of the pro-apoptotic process annotation; genuine but context-dependent and not the core function. Reason: Cell-death promotion by NIX is contextual and direction-dependent; secondary to mitophagy. Supporting Evidence: PMID:9973195 Overexpression of BNIP3alpha in transfected cells results in apoptosis and suppresses the antiapoptosis activity of E1B-19K and BCL-xL. |
| GO:0005515 protein binding | IPI PMID:10381623 A novel adenovirus E1B19K-binding protein B5 inhibits apopto... | REMOVE | Summary: Generic protein-binding annotation; the underlying B5 data describe specific self-association and BNIP3 heterodimerization, captured better by homodimerization activity. Reason: Bare protein binding conveys no functional information. The functionally informative activities of NIX are captured by GO:0140580 (mitochondrion autophagosome adaptor activity), GO:0042803 and GO:0042802. Removal does not imply the interaction is false. Supporting Evidence: PMID:10381623 B5 binds strongly to Nip3 and itself |
| GO:0005515 protein binding | IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in... | REMOVE | Summary: Protein binding with TMEM11 from a high-throughput interactome study; no functional context for NIX. Reason: Bare protein binding conveys no functional information. The functionally informative activities of NIX are captured by GO:0140580 (mitochondrion autophagosome adaptor activity), GO:0042803 and GO:0042802. Removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:19060904 An empirical framework for binary interactome mapping. | REMOVE | Summary: Protein binding with BNIP3 from a high-throughput interactome study; no functional context for NIX. Reason: Bare protein binding conveys no functional information. The functionally informative activities of NIX are captured by GO:0140580 (mitochondrion autophagosome adaptor activity), GO:0042803 and GO:0042802. Removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:21516116 Next-generation sequencing to generate interactome datasets. | REMOVE | Summary: Protein binding with BNIP3 from a high-throughput interactome study; no functional context for NIX. Reason: Bare protein binding conveys no functional information. The functionally informative activities of NIX are captured by GO:0140580 (mitochondrion autophagosome adaptor activity), GO:0042803 and GO:0042802. Removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:22645275 Identification of novel ATP13A2 interactors and their role i... | REMOVE | Summary: Protein binding with ATP13A2 from a high-throughput interactome study; no functional context for NIX. Reason: Bare protein binding conveys no functional information. The functionally informative activities of NIX are captured by GO:0140580 (mitochondrion autophagosome adaptor activity), GO:0042803 and GO:0042802. Removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:24316735 Orphan nuclear receptor TR3 acts in autophagic cell death vi... | REMOVE | Summary: Generic protein-binding annotation from a TR3/NR4A1 autophagic-cell-death study; uninformative as bare protein binding. Reason: Bare protein binding conveys no functional information. The functionally informative activities of NIX are captured by GO:0140580 (mitochondrion autophagosome adaptor activity), GO:0042803 and GO:0042802. Removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:24981860 Human-chromatin-related protein interactions identify a deme... | REMOVE | Summary: Protein binding with BNIP3 from a high-throughput interactome study; no functional context for NIX. Reason: Bare protein binding conveys no functional information. The functionally informative activities of NIX are captured by GO:0140580 (mitochondrion autophagosome adaptor activity), GO:0042803 and GO:0042802. Removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Protein binding with TMEM11 from a high-throughput interactome study; no functional context for NIX. Reason: Bare protein binding conveys no functional information. The functionally informative activities of NIX are captured by GO:0140580 (mitochondrion autophagosome adaptor activity), GO:0042803 and GO:0042802. Removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25910212 Widespread macromolecular interaction perturbations in human... | REMOVE | Summary: Protein binding with ADIPOQ from a high-throughput interactome study; no functional context for NIX. Reason: Bare protein binding conveys no functional information. The functionally informative activities of NIX are captured by GO:0140580 (mitochondrion autophagosome adaptor activity), GO:0042803 and GO:0042802. Removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:27107012 Pooled-matrix protein interaction screens using Barcode Fusi... | REMOVE | Summary: Protein binding with TMEM11 from a high-throughput interactome study; no functional context for NIX. Reason: Bare protein binding conveys no functional information. The functionally informative activities of NIX are captured by GO:0140580 (mitochondrion autophagosome adaptor activity), GO:0042803 and GO:0042802. Removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: Protein binding with BNIP3 from a high-throughput interactome study; no functional context for NIX. Reason: Bare protein binding conveys no functional information. The functionally informative activities of NIX are captured by GO:0140580 (mitochondrion autophagosome adaptor activity), GO:0042803 and GO:0042802. Removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | REMOVE | Summary: Protein binding with LDLRAD1 from a high-throughput interactome study; no functional context for NIX. Reason: Bare protein binding conveys no functional information. The functionally informative activities of NIX are captured by GO:0140580 (mitochondrion autophagosome adaptor activity), GO:0042803 and GO:0042802. Removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Protein binding with TMEM120B from a high-throughput interactome study; no functional context for NIX. Reason: Bare protein binding conveys no functional information. The functionally informative activities of NIX are captured by GO:0140580 (mitochondrion autophagosome adaptor activity), GO:0042803 and GO:0042802. Removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: Protein binding with BNIP3 from a high-throughput interactome study; no functional context for NIX. Reason: Bare protein binding conveys no functional information. The functionally informative activities of NIX are captured by GO:0140580 (mitochondrion autophagosome adaptor activity), GO:0042803 and GO:0042802. Removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:34845370 SARS-CoV-2 ORF10 suppresses the antiviral innate immune resp... | REMOVE | Summary: This protein-binding annotation reflects the specific, functionally important interaction of NIX with SARS-CoV-2 ORF10 and LC3B during virus-hijacked mitophagy; as bare protein binding it is uninformative. Reason: Bare protein binding conveys no functional information. The functionally informative activities of NIX are captured by GO:0140580 (mitochondrion autophagosome adaptor activity), GO:0042803 and GO:0042802. Removal does not imply the interaction is false. Supporting Evidence: PMID:34845370 ORF10 was translocated to mitochondria by interacting with the mitophagy receptor Nip3-like protein X (NIX) and induced mitophagy through its interaction with both NIX and LC3B |
| GO:0005515 protein binding | IPI PMID:39526800 A comprehensive two-hybrid analysis to explore the Legionell... | REMOVE | Summary: Protein binding with BNIP3 from a high-throughput interactome study; no functional context for NIX. Reason: Bare protein binding conveys no functional information. The functionally informative activities of NIX are captured by GO:0140580 (mitochondrion autophagosome adaptor activity), GO:0042803 and GO:0042802. Removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:9973195 BNIP3alpha: a human homolog of mitochondrial proapoptotic pr... | REMOVE | Summary: Generic protein-binding annotation; the underlying data describe specific interactions with E1B-19K, BCL-2 and BCL-xL, not informative as bare binding. Reason: Bare protein binding conveys no functional information. The functionally informative activities of NIX are captured by GO:0140580 (mitochondrion autophagosome adaptor activity), GO:0042803 and GO:0042802. Removal does not imply the interaction is false. Supporting Evidence: PMID:9973195 BNIP3alpha interacts with viral antiapoptosis protein E1B-19K and cellular antiapoptosis proteins BCL-2 and BCL-xL. |
| GO:0042802 identical protein binding | IPI PMID:10381623 A novel adenovirus E1B19K-binding protein B5 inhibits apopto... | ACCEPT | Summary: NIX/B5 self-associates, and the original study directly shows it binds itself; identical protein binding (self-association) is supported. Reason: Self-association is directly demonstrated and is a genuine, informative molecular property of NIX. Supporting Evidence: PMID:10381623 B5 binds strongly to Nip3 and itself |
| GO:0042802 identical protein binding | IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in... | ACCEPT | Summary: NIX self-association is recorded as identical protein binding in a high-throughput interactome (IntAct O60238-O60238); consistent with directly demonstrated self-association. Reason: NIX self-association is independently supported by direct biochemistry; the high-throughput identical-protein-binding hit is consistent and informative. Supporting Evidence: PMID:10381623 B5 binds strongly to Nip3 and itself |
| GO:0042802 identical protein binding | IPI PMID:21516116 Next-generation sequencing to generate interactome datasets. | ACCEPT | Summary: NIX self-association recorded as identical protein binding from interactome mapping; consistent with demonstrated self-association. Reason: Consistent with directly demonstrated NIX self-association and informative as a homodimerization property. Supporting Evidence: PMID:10381623 B5 binds strongly to Nip3 and itself |
| GO:0042802 identical protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | ACCEPT | Summary: NIX self-association recorded as identical protein binding from a proteome-scale interactome; consistent with demonstrated self-association. Reason: Consistent with directly demonstrated NIX self-association. Supporting Evidence: PMID:10381623 B5 binds strongly to Nip3 and itself |
| GO:0042802 identical protein binding | IPI PMID:27107012 Pooled-matrix protein interaction screens using Barcode Fusi... | ACCEPT | Summary: NIX self-association recorded as identical protein binding from a pooled interaction screen; consistent with demonstrated self-association. Reason: Consistent with directly demonstrated NIX self-association. Supporting Evidence: PMID:10381623 B5 binds strongly to Nip3 and itself |
| GO:0005739 mitochondrion | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: General mitochondrial localization; correct but less specific than the mitochondrial outer membrane localization. Reason: Accurate but subsumed by the more precise mitochondrial outer membrane annotation. Supporting Evidence: PMID:9973195 Like BNIP3, BNIP3alpha seems to be predominantly localized in mitochondria. |
| GO:0010917 negative regulation of mitochondrial membrane potential | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NIX/BNIP3 can affect mitochondrial membrane potential/permeability (linked to necrosis and to depolarization-triggered mitophagy), a contextual mitochondrial effect. Reason: Effects on membrane potential are documented but are a downstream/contextual aspect rather than the core mitophagy-receptor activity. Supporting Evidence: PMID:21264228 related to necrosis through the regulation of mitochondrial permeability transition pore (MPTP) |
| GO:0035794 positive regulation of mitochondrial membrane permeability | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NIX/BNIP3 are linked to opening of the mitochondrial permeability transition pore and necrosis-related membrane permeabilization, a contextual function. Reason: Supported as a contextual mitochondrial membrane effect; secondary to mitophagy-receptor activity. Supporting Evidence: PMID:21264228 related to necrosis through the regulation of mitochondrial permeability transition pore (MPTP) |
| GO:0042802 identical protein binding | IEA GO_REF:0000120 | ACCEPT | Summary: Automated identical-protein-binding annotation, consistent with directly demonstrated NIX self-association. Reason: Consistent with documented NIX self-association. Supporting Evidence: PMID:10381623 B5 binds strongly to Nip3 and itself |
| GO:1901524 regulation of mitophagy | IEA GO_REF:0000107 | ACCEPT | Summary: Regulation of mitophagy is a core process for NIX, which acts as a mitochondrial receptor connecting mitochondria to the autophagy machinery via LC3/GABARAP. Reason: Mitophagy is the defining conserved function of NIX and is strongly supported. Supporting Evidence: PMID:20200478 Nix is a mitochondrial receptor that can directly connect to one of the autophagic machinery components, the Atg8 homologs LC3 and GABARAP. |
| GO:1903747 regulation of protein localization to mitochondrion | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: NIX recruits autophagy machinery (LC3/GABARAP) to mitochondria; this can be viewed as regulating protein localization to the mitochondrion, but it is better represented by mitophagy receptor activity. Reason: The annotation captures a mechanistic aspect (recruitment of Atg8-family proteins to mitochondria) of the core mitophagy function but as a broad regulatory term is less precise; retained as non-core. Supporting Evidence: PMID:20200478 Nix is a mitochondrial receptor that can directly connect to one of the autophagic machinery components, the Atg8 homologs LC3 and GABARAP. |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: Immunofluorescence-based mitochondrial localization, consistent with the predominant mitochondrial localization of NIX. Reason: Accurate but subsumed by the more precise mitochondrial outer membrane localization. Supporting Evidence: PMID:9973195 Like BNIP3, BNIP3alpha seems to be predominantly localized in mitochondria. |
| GO:0016607 nuclear speck | IDA GO_REF:0000052 | MARK AS OVER ANNOTATED | Summary: A nuclear speck localization (HPA immunofluorescence) is weakly supported and inconsistent with the established tail-anchored mitochondrial outer membrane biology of NIX. Reason: No defined nuclear-speck function exists for NIX; this single-source localization likely reflects antibody/overexpression artifact and is not the functional compartment. |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | KEEP AS NON CORE | Summary: High-throughput mitochondrial proteome localization, consistent with NIX being a mitochondrial protein. Reason: Accurate but subsumed by the more precise mitochondrial outer membrane localization. Supporting Evidence: PMID:34800366 mitochondrial proteome |
| GO:0043069 negative regulation of programmed cell death | IGI PMID:19273585 Hypoxia-induced autophagy is mediated through hypoxia-induci... | KEEP AS NON CORE | Summary: Under hypoxia, HIF-induced BNIP3/BNIP3L promote pro-survival autophagy and their ablation triggers cell death, supporting a negative regulation of programmed cell death role in this context. Reason: Supported by genetic evidence but contextual (hypoxia/survival); secondary to the core mitophagy-receptor function. Supporting Evidence: PMID:19273585 the ablation of BNIP3 and/or BNIP3L triggers cell death PMID:19273585 Hypoxia-induced autophagy via BNIP3 and BNIP3L is clearly a survival mechanism that promotes tumor progression. |
| GO:0016239 positive regulation of macroautophagy | IGI PMID:19273585 Hypoxia-induced autophagy is mediated through hypoxia-induci... | ACCEPT | Summary: BNIP3/BNIP3L are required for hypoxia-induced macroautophagy and their atypical BH3 domains can initiate autophagy by disrupting the Bcl-2-Beclin1 complex. Reason: Positive regulation of macroautophagy is well supported by combined silencing/ectopic expression and BH3-peptide experiments, and is closely tied to the autophagy-receptor biology of NIX. Supporting Evidence: PMID:19273585 the combined silencing of these two HIF targets suppresses hypoxia-mediated autophagy PMID:19273585 the ectopic expression of both BNIP3 and BNIP3L in normoxia activates autophagy |
| GO:0071456 cellular response to hypoxia | IGI PMID:19273585 Hypoxia-induced autophagy is mediated through hypoxia-induci... | KEEP AS NON CORE | Summary: BNIP3L is a HIF target that mediates hypoxia-induced autophagy, supporting a role in the cellular response to hypoxia. Reason: Supported as part of the hypoxia/HIF-autophagy axis but is a contextual upstream process rather than the core molecular function. Supporting Evidence: PMID:19273585 the combined silencing of these two HIF targets suppresses hypoxia-mediated autophagy |
| GO:0005741 mitochondrial outer membrane | TAS Reactome:R-HSA-6798004 | ACCEPT | Summary: Reactome-curated mitochondrial outer membrane localization (TP53 stimulates BNIP3L expression pathway). Reason: Consistent with the well-supported core localization. Supporting Evidence: PMID:20200478 Nix is a mitochondrial outer membrane protein that is required for mitochondrial clearance during erythrocyte maturation. |
| GO:0005741 mitochondrial outer membrane | TAS Reactome:R-HSA-6801195 | ACCEPT | Summary: Reactome-curated mitochondrial outer membrane localization (STEAP3 binds BNIP3L pathway). Reason: Consistent with the well-supported core localization. Supporting Evidence: PMID:20200478 Nix is a mitochondrial outer membrane protein that is required for mitochondrial clearance during erythrocyte maturation. |
| GO:0005515 protein binding | IPI PMID:20200478 Nix, a receptor protein for mitophagy in mammals. | REMOVE | Summary: IPI with ATG13, cited from Kanki 2010 (Autophagy commentary on NIX as a mitophagy receptor). ATG13 binding is not the LC3/GABARAP adaptor interaction and is not interpreted in the cited abstract. Reason: Bare protein binding conveys no functional information. The functionally informative activities of NIX are captured by GO:0140580 (mitochondrion autophagosome adaptor activity), GO:0042803 and GO:0042802. Removal does not imply the interaction is false. Supporting Evidence: PMID:20200478 Nix is a mitochondrial receptor that can directly connect to one of the autophagic machinery components, the Atg8 homologs LC3 and GABARAP. |
| GO:0043065 positive regulation of apoptotic process | IDA PMID:9973195 BNIP3alpha: a human homolog of mitochondrial proapoptotic pr... | KEEP AS NON CORE | Summary: Overexpression of BNIP3alpha induced apoptosis in transfected cells, providing direct (if overexpression-based) evidence for a pro-apoptotic role. Reason: Direct evidence supports a pro-apoptotic capacity, but it is context-dependent/overexpression-driven and secondary to the conserved mitophagy function. Supporting Evidence: PMID:9973195 Overexpression of BNIP3alpha in transfected cells results in apoptosis and suppresses the antiapoptosis activity of E1B-19K and BCL-xL. |
| GO:0005515 protein binding | IPI PMID:21264221 Possible existence of lysosome-like organella within mitocho... | REMOVE | Summary: Generic protein-binding annotation associated with the Mieap/MALM mitochondrial quality-control studies; uninformative as bare binding. Reason: Bare protein binding conveys no functional information. The functionally informative activities of NIX are captured by GO:0140580 (mitochondrion autophagosome adaptor activity), GO:0042803 and GO:0042802. Removal does not imply the interaction is false. |
| GO:0005741 mitochondrial outer membrane | IMP PMID:21264228 Mieap, a p53-inducible protein, controls mitochondrial quali... | ACCEPT | Summary: NIX localizes to and acts at the mitochondrial outer membrane, where it interacts with Mieap via its BH3 domain; mutational/localization analysis supports this compartment. Reason: Directly supported core localization. Supporting Evidence: PMID:21264228 A mitochondrial outer membrane protein NIX interacted with Mieap in a ROS-dependent manner via the BH3 domain of NIX and the coiled-coil domain of Mieap. |
| GO:0035694 mitochondrial protein catabolic process | IMP PMID:21264228 Mieap, a p53-inducible protein, controls mitochondrial quali... | ACCEPT | Summary: NIX is an essential mediator of MALM (Mieap-induced accumulation of lysosome-like organelles within mitochondria), a non-canonical process that degrades oxidized mitochondrial proteins; NIX deficiency impairs MALM. Reason: Loss-of-function (NIX knockdown) directly impairs MALM, supporting NIX involvement in mitochondrial protein catabolism within the mitochondrial quality-control context. Supporting Evidence: PMID:21264228 Deficiency of NIX also completely impaired MALM. |
| GO:0005521 lamin binding | IPI PMID:10381623 A novel adenovirus E1B19K-binding protein B5 inhibits apopto... | KEEP AS NON CORE | Summary: Lamin binding derives from the original B5/nuclear-envelope study; it is a specific but secondary interaction not central to the mitophagy-receptor function. Reason: Retained as a specific (non-generic) binding annotation, but it is contextual to the nuclear-envelope localization and not the core function. Supporting Evidence: PMID:10381623 localizes in nuclear envelope, endoplasmic reticulum and mitochondria |
| GO:0005521 lamin binding | IDA PMID:10381623 A novel adenovirus E1B19K-binding protein B5 inhibits apopto... | KEEP AS NON CORE | Summary: Direct-assay lamin binding from the original B5 study; specific but secondary. Reason: Specific binding annotation tied to nuclear-envelope localization; not the core function. Supporting Evidence: PMID:10381623 localizes in nuclear envelope, endoplasmic reticulum and mitochondria |
| GO:0005635 nuclear envelope | IDA PMID:10381623 A novel adenovirus E1B19K-binding protein B5 inhibits apopto... | KEEP AS NON CORE | Summary: Direct localization of B5/NIX to the nuclear envelope in the original study; secondary site. Reason: Documented but secondary localization relative to the mitochondrial outer membrane. Supporting Evidence: PMID:10381623 localizes in nuclear envelope, endoplasmic reticulum and mitochondria |
| GO:0005739 mitochondrion | IDA PMID:10381623 A novel adenovirus E1B19K-binding protein B5 inhibits apopto... | KEEP AS NON CORE | Summary: Direct mitochondrial localization in the original B5 study. Reason: Accurate but subsumed by the more precise mitochondrial outer membrane localization. Supporting Evidence: PMID:10381623 localizes in nuclear envelope, endoplasmic reticulum and mitochondria |
| GO:0005783 endoplasmic reticulum | IDA PMID:10381623 A novel adenovirus E1B19K-binding protein B5 inhibits apopto... | KEEP AS NON CORE | Summary: Direct ER localization in the original B5 study; secondary site. Reason: Documented but secondary localization relative to the mitochondrial outer membrane. ORGANELLES check (2026-11-04, ER batch 1). PMID:10381623 is abstract-only here, so whether the B5 imaging used an ER marker or tagged overexpressed protein cannot be checked; the curator read the full text, and endogenous NIX at the ER/SR in mouse heart (PMID:19065046) independently supports the organelle. Direct evidence that cannot resolve the sub-compartment, peripheral to the mitophagy-receptor function, so KEEP_AS_NON_CORE. Supporting Evidence: PMID:10381623 localizes in nuclear envelope, endoplasmic reticulum and mitochondria PMID:19065046 Endogenous cardiac NIX and recombinant NIX localize both to the mitochondria and to the ER/SR. |
| GO:0005789 endoplasmic reticulum membrane | IC PMID:19065046 Endoplasmic reticulum-mitochondria crosstalk in NIX-mediated... | NEW | Summary: Proposed sub-compartment. The ER pool of NIX is held by its C-terminal tail anchor, so it is an ER-membrane pool; the existing annotations stop at the organelle. Reason: ORGANELLES rule 4 (2026-11-04, ER batch 1). Lines that agree on the membrane rather than the lumen. (1) Topology - NIX has a single C-terminal helical TM segment (188-208) and no signal peptide, and UniProt records it as a single-pass membrane protein, so an ER pool cannot be lumenal and must be membrane-inserted with the LIR/BH3-containing N-terminus in the cytosol. (2) Function - the ER/SR pool of NIX controls ER/SR Ca2+ content and signals to mitochondria (PMID:19065046), an activity at the cytosolic face of the ER membrane. (3) Phylogeny - PANTHER PTHR15186 has a PAINT IBD for GO:0005789 at PTN002689498, seeded by the paralog BNIP3, whose ER-membrane location is direct-assay supported; BNIP3L is not under that node, so this is a paralog comparator, not a propagation. IC because the TM is predicted and no membrane-extraction or protease-protection assay of the ER pool was done. The ER pool is not core, so core_functions are unchanged; the MAM and the nuclear envelope are not asserted. Supporting Evidence: file:human/BNIP3L/BNIP3L-uniprot.txt FT TRANSMEM 188..208 FT /note="Helical" file:human/BNIP3L/BNIP3L-uniprot.txt Membrane {ECO:0000305}; Single-pass PMID:19065046 In genetic mouse models, cardiomyocyte ER/SR calcium stores are proportional to the level of expressed NIX. |
| GO:0016020 membrane | TAS PMID:10381623 A novel adenovirus E1B19K-binding protein B5 inhibits apopto... | MARK AS OVER ANNOTATED | Summary: NIX/B5 contains a C-terminal transmembrane region; generic membrane localization is correct but uninformative. Reason: Subsumed by the specific mitochondrial outer membrane localization. Supporting Evidence: PMID:10381623 contains the putative BH3 and transmembrane regions |
| GO:0042803 protein homodimerization activity | IDA PMID:10381623 A novel adenovirus E1B19K-binding protein B5 inhibits apopto... | ACCEPT | Summary: NIX/B5 self-associates (binds itself), supporting protein homodimerization activity as a genuine molecular property. Reason: Directly demonstrated self-association; informative homodimerization activity. Supporting Evidence: PMID:10381623 B5 binds strongly to Nip3 and itself |
| GO:0043066 negative regulation of apoptotic process | IDA PMID:10381623 A novel adenovirus E1B19K-binding protein B5 inhibits apopto... | KEEP AS NON CORE | Summary: In the original B5 study, NIX did not itself induce apoptosis but inhibited Nip3(BNIP3)-induced apoptosis, supporting an anti-apoptotic capacity in this context. Reason: This anti-apoptotic effect is genuine but direction- and context-dependent (the same protein can also promote death); secondary to mitophagy. Supporting Evidence: PMID:10381623 B5 does not induce apoptosis, but inhibits apoptosis induced by Nip3 |
| GO:0005739 mitochondrion | IDA PMID:9973195 BNIP3alpha: a human homolog of mitochondrial proapoptotic pr... | KEEP AS NON CORE | Summary: Direct mitochondrial localization of BNIP3alpha/NIX. Reason: Accurate but subsumed by the more precise mitochondrial outer membrane localization. Supporting Evidence: PMID:9973195 Like BNIP3, BNIP3alpha seems to be predominantly localized in mitochondria. |
| GO:0051607 defense response to virus | IDA PMID:9973195 BNIP3alpha: a human homolog of mitochondrial proapoptotic pr... | REMOVE | Summary: The cited 1999 BNIP3alpha paper is about apoptosis/anti-apoptotic-protein interactions and does not provide direct evidence for defense response to virus; the genuine antiviral connection (NIX-mediated mitophagy degrading MAVS) is established by later work, but viruses hijack this for immune evasion rather than NIX acting in host antiviral defense. Reason: The original reference (PMID:9973195) was reviewed and is about apoptosis/anti-apoptotic-protein interactions; it provides no evidence for a defense-response-to-virus role (this is therefore a removal on reviewed evidence, not an UNDECIDED due to inaccessible literature). Later literature (PMID:34845370) shows NIX-mediated mitophagy is hijacked by SARS-CoV-2 ORF10 to degrade MAVS and suppress innate immunity, the opposite of host antiviral defense; KSHV vIRF-1 similarly co-opts NIX. The annotation is unlikely to be correct based on the combined evidence. Supporting Evidence: PMID:34845370 ORF10 was translocated to mitochondria by interacting with the mitophagy receptor Nip3-like protein X (NIX) and induced mitophagy through its interaction with both NIX and LC3B PMID:34845370 NIX-mediated mitophagy is responsible for the elimination of spontaneously aggregated MAVS |
| GO:0140580 mitochondrion autophagosome adaptor activity | IDA PMID:20010802 Nix is a selective autophagy receptor for mitochondrial clea... | NEW | Summary: NIX/BNIP3L is a mitochondrial outer-membrane mitophagy receptor that links mitochondria to Atg8-family proteins LC3 and GABARAP. Reason: NIX itself performs the adaptor step. It sits in the mitochondrial outer membrane and binds LC3/GABARAP through its LIR, tethering mitochondria to forming autophagosomes, which is the definition of GO:0140580. This existing term covers the activity, so no new "mitophagy receptor activity" term is needed. Supporting Evidence: PMID:20010802 Here, we show that the mitochondrial protein Nix is a selective autophagy receptor by binding to LC3/GABARAP proteins file:human/BNIP3L/BNIP3L-deep-research-falcon.md that links mitochondria to the autophagy machinery to drive mitophagy |
| GO:0005515 protein binding | IPI PMID:10381623 A novel adenovirus E1B19K-binding protein B5 inhibits apopto... | REMOVE | Summary: IPI with BNIP2. Reason: Bare protein binding conveys no functional information. The functionally informative activities of NIX are captured by GO:0140580 (mitochondrion autophagosome adaptor activity), GO:0042803 and GO:0042802. Removal does not imply the interaction is false. Supporting Evidence: PMID:10381623 B5 binds strongly to Nip3 and itself, weakly to E1B19K, but not to Bcl-2 |
| GO:0005515 protein binding | IPI PMID:10381623 A novel adenovirus E1B19K-binding protein B5 inhibits apopto... | REMOVE | Summary: IPI with BNIP3. Reason: Bare protein binding conveys no functional information. The functionally informative activities of NIX are captured by GO:0140580 (mitochondrion autophagosome adaptor activity), GO:0042803 and GO:0042802. Removal does not imply the interaction is false. Supporting Evidence: PMID:10381623 B5 binds strongly to Nip3 and itself, weakly to E1B19K, but not to Bcl-2 |
| GO:0005515 protein binding | IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in... | REMOVE | Summary: Protein binding with BNIP3 from a high-throughput interactome study; no functional context for NIX. Reason: Bare protein binding conveys no functional information. The functionally informative activities of NIX are captured by GO:0140580 (mitochondrion autophagosome adaptor activity), GO:0042803 and GO:0042802. Removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:20200478 Nix, a receptor protein for mitophagy in mammals. | MODIFY | Summary: IPI with the Atg8-family protein GABARAP, cited from Kanki 2010 (Autophagy), which describes NIX as a mitochondrial outer membrane receptor that directly connects to LC3 and GABARAP. Binding of an OMM protein to an autophagosome-anchored Atg8 protein is the defining step of mitophagy-receptor activity. Reason: Bare protein binding is uninformative, but here the cited work (and the primary study PMID:20010802) places the interaction in its functional context: NIX binds LC3/GABARAP through its LIR to tether mitochondria to autophagosomes. The informative MF is mitochondrion autophagosome adaptor activity, already proposed as NEW from PMID:20010802. Proposed replacements: mitochondrion autophagosome adaptor activity Supporting Evidence: PMID:20200478 Nix is a mitochondrial receptor that can directly connect to one of the autophagic machinery components, the Atg8 homologs LC3 and GABARAP. PMID:20010802 Nix is a selective autophagy receptor for mitochondrial clearance. |
| GO:0005515 protein binding | IPI PMID:20200478 Nix, a receptor protein for mitophagy in mammals. | REMOVE | Summary: IPI with yeast Atg8, cited from Kanki 2010 (Autophagy commentary on NIX as a mitophagy receptor). Yeast Atg8 is a heterologous partner; the physiologically relevant LC3/GABARAP rows from this paper are modified to GO:0140580. Reason: Bare protein binding conveys no functional information. The functionally informative activities of NIX are captured by GO:0140580 (mitochondrion autophagosome adaptor activity), GO:0042803 and GO:0042802. Removal does not imply the interaction is false. Supporting Evidence: PMID:20200478 Nix is a mitochondrial receptor that can directly connect to one of the autophagic machinery components, the Atg8 homologs LC3 and GABARAP. |
| GO:0005515 protein binding | IPI PMID:20200478 Nix, a receptor protein for mitophagy in mammals. | MODIFY | Summary: IPI with the Atg8-family protein MAP1LC3B, cited from Kanki 2010 (Autophagy), which describes NIX as a mitochondrial outer membrane receptor that directly connects to LC3 and GABARAP. Binding of an OMM protein to an autophagosome-anchored Atg8 protein is the defining step of mitophagy-receptor activity. Reason: Bare protein binding is uninformative, but here the cited work (and the primary study PMID:20010802) places the interaction in its functional context: NIX binds LC3/GABARAP through its LIR to tether mitochondria to autophagosomes. The informative MF is mitochondrion autophagosome adaptor activity, already proposed as NEW from PMID:20010802. Proposed replacements: mitochondrion autophagosome adaptor activity Supporting Evidence: PMID:20200478 Nix is a mitochondrial receptor that can directly connect to one of the autophagic machinery components, the Atg8 homologs LC3 and GABARAP. PMID:20010802 Nix is a selective autophagy receptor for mitochondrial clearance. |
| GO:0005515 protein binding | IPI PMID:21516116 Next-generation sequencing to generate interactome datasets. | REMOVE | Summary: Protein binding with CLEC7A from a high-throughput interactome study; no functional context for NIX. Reason: Bare protein binding conveys no functional information. The functionally informative activities of NIX are captured by GO:0140580 (mitochondrion autophagosome adaptor activity), GO:0042803 and GO:0042802. Removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:21516116 Next-generation sequencing to generate interactome datasets. | REMOVE | Summary: Protein binding with SMCO4 from a high-throughput interactome study; no functional context for NIX. Reason: Bare protein binding conveys no functional information. The functionally informative activities of NIX are captured by GO:0140580 (mitochondrion autophagosome adaptor activity), GO:0042803 and GO:0042802. Removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Protein binding with BNIP3 from a high-throughput interactome study; no functional context for NIX. Reason: Bare protein binding conveys no functional information. The functionally informative activities of NIX are captured by GO:0140580 (mitochondrion autophagosome adaptor activity), GO:0042803 and GO:0042802. Removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Protein binding with LDLRAD1 from a high-throughput interactome study; no functional context for NIX. Reason: Bare protein binding conveys no functional information. The functionally informative activities of NIX are captured by GO:0140580 (mitochondrion autophagosome adaptor activity), GO:0042803 and GO:0042802. Removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Protein binding with FATE1 from a high-throughput interactome study; no functional context for NIX. Reason: Bare protein binding conveys no functional information. The functionally informative activities of NIX are captured by GO:0140580 (mitochondrion autophagosome adaptor activity), GO:0042803 and GO:0042802. Removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Protein binding with CLEC7A from a high-throughput interactome study; no functional context for NIX. Reason: Bare protein binding conveys no functional information. The functionally informative activities of NIX are captured by GO:0140580 (mitochondrion autophagosome adaptor activity), GO:0042803 and GO:0042802. Removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: Protein binding with SMCO4 from a high-throughput interactome study; no functional context for NIX. Reason: Bare protein binding conveys no functional information. The functionally informative activities of NIX are captured by GO:0140580 (mitochondrion autophagosome adaptor activity), GO:0042803 and GO:0042802. Removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:27107012 Pooled-matrix protein interaction screens using Barcode Fusi... | REMOVE | Summary: Protein binding with BNIP3 from a high-throughput interactome study; no functional context for NIX. Reason: Bare protein binding conveys no functional information. The functionally informative activities of NIX are captured by GO:0140580 (mitochondrion autophagosome adaptor activity), GO:0042803 and GO:0042802. Removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Protein binding with CYB5B from a high-throughput interactome study; no functional context for NIX. Reason: Bare protein binding conveys no functional information. The functionally informative activities of NIX are captured by GO:0140580 (mitochondrion autophagosome adaptor activity), GO:0042803 and GO:0042802. Removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Protein binding with TMEM11 from a high-throughput interactome study; no functional context for NIX. Reason: Bare protein binding conveys no functional information. The functionally informative activities of NIX are captured by GO:0140580 (mitochondrion autophagosome adaptor activity), GO:0042803 and GO:0042802. Removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Protein binding with GABARAPL2 from a high-throughput interactome study; no functional context for NIX. Reason: Bare protein binding conveys no functional information. The functionally informative activities of NIX are captured by GO:0140580 (mitochondrion autophagosome adaptor activity), GO:0042803 and GO:0042802. Removal does not imply the interaction is false. The Y2H hit with an Atg8-family protein is consistent with the known LIR, but a binary screen does not show adaptor activity on mitochondria, so no MF upgrade is made. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Protein binding with BNIP3 from a high-throughput interactome study; no functional context for NIX. Reason: Bare protein binding conveys no functional information. The functionally informative activities of NIX are captured by GO:0140580 (mitochondrion autophagosome adaptor activity), GO:0042803 and GO:0042802. Removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Protein binding with MALL from a high-throughput interactome study; no functional context for NIX. Reason: Bare protein binding conveys no functional information. The functionally informative activities of NIX are captured by GO:0140580 (mitochondrion autophagosome adaptor activity), GO:0042803 and GO:0042802. Removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Protein binding with CLEC7A isoform 6 from a high-throughput interactome study; no functional context for NIX. Reason: Bare protein binding conveys no functional information. The functionally informative activities of NIX are captured by GO:0140580 (mitochondrion autophagosome adaptor activity), GO:0042803 and GO:0042802. Removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Protein binding with GABARAPL1 from a high-throughput interactome study; no functional context for NIX. Reason: Bare protein binding conveys no functional information. The functionally informative activities of NIX are captured by GO:0140580 (mitochondrion autophagosome adaptor activity), GO:0042803 and GO:0042802. Removal does not imply the interaction is false. The Y2H hit with an Atg8-family protein is consistent with the known LIR, but a binary screen does not show adaptor activity on mitochondria, so no MF upgrade is made. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Protein binding with TNMD isoform 2 from a high-throughput interactome study; no functional context for NIX. Reason: Bare protein binding conveys no functional information. The functionally informative activities of NIX are captured by GO:0140580 (mitochondrion autophagosome adaptor activity), GO:0042803 and GO:0042802. Removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Protein binding with SMCO4 from a high-throughput interactome study; no functional context for NIX. Reason: Bare protein binding conveys no functional information. The functionally informative activities of NIX are captured by GO:0140580 (mitochondrion autophagosome adaptor activity), GO:0042803 and GO:0042802. Removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Protein binding with TMPRSS4 from a high-throughput interactome study; no functional context for NIX. Reason: Bare protein binding conveys no functional information. The functionally informative activities of NIX are captured by GO:0140580 (mitochondrion autophagosome adaptor activity), GO:0042803 and GO:0042802. Removal does not imply the interaction is false. |
| GO:0005515 protein binding | IPI PMID:9973195 BNIP3alpha: a human homolog of mitochondrial proapoptotic pr... | REMOVE | Summary: IPI with BCL2. Reason: Bare protein binding conveys no functional information. The functionally informative activities of NIX are captured by GO:0140580 (mitochondrion autophagosome adaptor activity), GO:0042803 and GO:0042802. Removal does not imply the interaction is false. Supporting Evidence: PMID:9973195 BNIP3alpha interacts with viral antiapoptosis protein E1B-19K and cellular antiapoptosis proteins BCL-2 and BCL-xL. |
| GO:0005515 protein binding | IPI PMID:9973195 BNIP3alpha: a human homolog of mitochondrial proapoptotic pr... | REMOVE | Summary: IPI with BAD. Reason: Bare protein binding conveys no functional information. The functionally informative activities of NIX are captured by GO:0140580 (mitochondrion autophagosome adaptor activity), GO:0042803 and GO:0042802. Removal does not imply the interaction is false. Supporting Evidence: PMID:9973195 BNIP3alpha interacts with viral antiapoptosis protein E1B-19K and cellular antiapoptosis proteins BCL-2 and BCL-xL. |
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Download this section (compressed HTML)Q: Does human NIX have a genuine host-protective antiviral function, or is NIX-mediated mitophagy primarily a target that diverse viruses hijack (e.g., SARS-CoV-2 ORF10, KSHV vIRF-1) to degrade MAVS and evade innate immunity?
Suggested experts: He H, Choi YB
Q: How is the balance between NIX-driven pro-survival mitophagy and NIX-associated cell death (necrosis/membrane permeabilization) controlled in a given cell type and stress context?
Suggested experts: Mazure NM, Dorn GW
Q: To what extent is NIX-mediated pexophagy a distinct cargo-selection program versus a by-product of shared upstream (iron-chelation/HIF) signaling, and is the peroxisomal pool of NIX targeted or regulated differently from the mitochondrial pool?
Suggested experts: Ganley IG, Boya P
Q: Is the FBXL4/PPTC7-mediated constitutive turnover of NIX a general rheostat for basal mitophagy across tissues, and does failure of this turnover (e.g., FBXL4 variants) cause disease specifically through NIX rather than BNIP3 accumulation?
Suggested experts: Pagan JK, Niemi NM
Experiment: Compare wild-type NIX with LIR-motif point mutants (abolishing LC3/GABARAP binding) for their ability to rescue mitochondrial clearance during reticulocyte maturation and stress-induced mitophagy in NIX-null cells, using flow cytometry of mitochondrial mass and mito-Keima/mito-QC reporters.
Hypothesis: NIX functions as an LIR-dependent mitophagy receptor whose Atg8-family binding is required for programmed mitochondrial clearance.
Type: structure-function rescue and mitophagy flux assay
Experiment: Knock out NIX in cells and measure MAVS levels, type I interferon induction, and viral replication with and without virus-encoded mitophagy inducers (e.g., ORF10), distinguishing host-protective versus virus-exploited roles.
Hypothesis: NIX-mediated mitophagy is required for MAVS turnover and shapes innate antiviral signaling.
Type: loss-of-function antiviral signaling assay
Experiment: In NIX-null cells reconstituted with wild-type versus LIR-mutant NIX, quantify pexophagy flux (pexo-QC/pexophagy reporters and peroxisomal marker PMP70 loss) under iron chelation and during cardiomyocyte/erythroid differentiation, and use organelle fractionation plus targeted (peroxisome- vs mitochondria-restricted) NIX constructs to test whether peroxisomal cargo selection is separable from mitochondrial mitophagy.
Hypothesis: NIX acts as a selective autophagy receptor for peroxisomes (pexophagy) in addition to mitochondria, using a peroxisome-localized pool distinct from its mitochondrial pool.
Type: structure-function rescue and selective-autophagy flux assay
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