BCL2L13 (Bcl-rambo, Mil1) is a tail-anchored mitochondrial outer-membrane protein of the BCL-2 family that contains all four BCL-2 homology motifs (BH1-BH4) plus a unique ~250-residue insertion with tandem repeats preceding its C-terminal transmembrane anchor. It is the mammalian functional homolog of the yeast mitophagy receptor Atg32: through an LC3-interacting region it binds Atg8-family proteins (LC3/GABARAP, including GABARAPL2) to recruit the autophagy machinery to mitochondria, promoting mitochondrial fragmentation and selective autophagy of mitochondria (mitophagy) independently of the canonical DRP1 fission machinery. BCL2L13 was originally described as a pro-apoptotic BCL-2 homolog whose cell-death activity, which can promote caspase-3 activation, is conferred by its membrane-anchored C-terminal region rather than its BH motifs; unlike most BCL-2-family members it does not heterodimerize with other family members. It is broadly expressed (notably in heart, placenta, pancreas and skeletal muscle) and is targeted by the Legionella pneumophila effector SidF, which neutralizes it to block host apoptosis. A short nuclear-localized splice isoform lacking the transmembrane anchor also exists.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: BCL2L13 is a mitochondrial protein that acts at the mitochondrion (mitophagy receptor and pro-apoptotic activity at the mitochondrial outer membrane). Reason: Mitochondrial localization/activity is strongly and consistently supported; the mitochondrion is the principal functional compartment. Supporting Evidence: PMID:11262395 Bcl-rambo was localized to mitochondria file:human/BCL2L13/BCL2L13-uniprot.txt SUBCELLULAR LOCATION: [Isoform 2]: Mitochondrion membrane |
| GO:0016020 membrane | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: BCL2L13 is a single-pass tail-anchored membrane protein; generic membrane localization is correct but uninformative relative to the specific mitochondrial membrane. Reason: The generic membrane term is subsumed by the more specific and well-supported mitochondrial (outer) membrane localization. Supporting Evidence: file:human/BCL2L13/BCL2L13-uniprot.txt Single-pass membrane protein |
| GO:0005634 nucleus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: A nuclear localization is reported in UniProt, largely for the truncated isoform 1 that lacks the transmembrane anchor; it is secondary to the mitochondrial role. Reason: Nuclear localization is documented (especially for the short nuclear isoform) but is not the functional compartment for the conserved mitophagy/mitochondrial activities. Supporting Evidence: file:human/BCL2L13/BCL2L13-uniprot.txt SUBCELLULAR LOCATION: [Isoform 1]: Nucleus |
| GO:0006915 apoptotic process | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: BCL2L13/Bcl-rambo can promote apoptosis (originally described as a pro-apoptotic BCL-2 homolog), an InterPro-based transfer consistent with the experimental literature. Reason: A pro-apoptotic capacity is genuine but context/overexpression-dependent and secondary to the conserved mitophagy-receptor function. Supporting Evidence: PMID:11262395 its overexpression induces apoptosis that is specifically blocked by the caspase inhibitors, IAPs |
| GO:0031966 mitochondrial membrane | IEA GO_REF:0000044 | ACCEPT | Summary: BCL2L13 is anchored in the mitochondrial membrane (outer membrane), consistent with its tail-anchor and UniProt subcellular location. Reason: Well-supported core localization; the mitochondrial membrane is where BCL2L13 acts. Supporting Evidence: file:human/BCL2L13/BCL2L13-uniprot.txt SUBCELLULAR LOCATION: [Isoform 2]: Mitochondrion membrane |
| GO:0042981 regulation of apoptotic process | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: As a BCL-2-family protein with pro-apoptotic activity, BCL2L13 participates in regulation of apoptosis; an InterPro-based transfer consistent with the literature. Reason: Supported by the apoptosis literature but context-dependent and secondary to the mitophagy-receptor function. Supporting Evidence: PMID:11262395 Bcl-rambo constitutes a novel type of pro-apoptotic Bcl-2 member that triggers cell death independently of its BH motifs. |
| GO:0005515 protein binding | IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in... | MARK AS OVER ANNOTATED | Summary: High-throughput interactome protein-binding annotation; uninformative for BCL2L13 function. Reason: Generic protein binding from a proteome-scale interaction map does not identify an interpretable BCL2L13 function. |
| GO:0005515 protein binding | IPI PMID:17360363 Legionella pneumophila inhibits macrophage apoptosis by targ... | MARK AS OVER ANNOTATED | Summary: This protein-binding annotation reflects the specific interaction of Bcl-rambo with the Legionella effector SidF (which neutralizes it to block host apoptosis); as bare protein binding it is uninformative. Reason: The underlying SidF interaction is meaningful and confirms Bcl-rambo as a pro-death host target, but the generic protein binding term does not capture this; no specific GO binding term for a bacterial effector applies. Supporting Evidence: PMID:17360363 SidF contributes to apoptosis resistance in L. pneumophila-infected cells by specifically interacting with and neutralizing the effects of BNIP3 and Bcl-rambo, two proapoptotic members of Bcl2 protein family. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: High-throughput interactome protein-binding annotation; uninformative for BCL2L13 function. Reason: Generic protein binding from a proteome-scale interactome map is not functionally specific. |
| GO:0005515 protein binding | IPI PMID:25910212 Widespread macromolecular interaction perturbations in human... | MARK AS OVER ANNOTATED | Summary: High-throughput interactome protein-binding annotation; uninformative for BCL2L13 function. Reason: Generic protein binding from a disease-interactome perturbation study is not functionally specific. |
| GO:0005515 protein binding | IPI PMID:26871637 Widespread Expansion of Protein Interaction Capabilities by ... | MARK AS OVER ANNOTATED | Summary: High-throughput alternative-splicing interactome protein-binding annotation; uninformative for BCL2L13 function. Reason: Generic protein binding from a large-scale splicing-interactome study is not functionally specific. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MARK AS OVER ANNOTATED | Summary: High-throughput interactome protein-binding annotation; uninformative for BCL2L13 function. Reason: Generic protein binding from a large-scale interactome study is not functionally specific. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: High-throughput interactome protein-binding annotation; uninformative for BCL2L13 function. Reason: Generic protein binding from a reference binary interactome map is not functionally specific. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MARK AS OVER ANNOTATED | Summary: High-throughput neurodegenerative-disease interactome protein-binding annotation; uninformative for BCL2L13 function. Reason: Generic protein binding from a disease-interactome study is not functionally specific. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: High-throughput interactome protein-binding annotation; uninformative for BCL2L13 function. Reason: Generic protein binding from a cell-specific interactome remodeling study is not functionally specific. |
| GO:0005739 mitochondrion | IEA GO_REF:0000107 | ACCEPT | Summary: Orthology-based transfer of mitochondrial activity, consistent with the well-supported mitochondrial localization/function of BCL2L13. Reason: Consistent with the core mitochondrial compartment where BCL2L13 acts. Supporting Evidence: PMID:11262395 Bcl-rambo was localized to mitochondria |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | ACCEPT | Summary: Immunofluorescence-based mitochondrial localization, consistent with the literature. Reason: Directly supported core localization. Supporting Evidence: PMID:11262395 Bcl-rambo was localized to mitochondria |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: High-throughput mitochondrial proteome localization, consistent with BCL2L13 being a mitochondrial protein. Reason: Consistent with the well-supported core mitochondrial localization. Supporting Evidence: PMID:34800366 mitochondrial proteome |
| GO:0006915 apoptotic process | NAS PMID:11262395 Bcl-rambo, a novel Bcl-2 homologue that induces apoptosis vi... | KEEP AS NON CORE | Summary: The founding Bcl-rambo study reports that overexpression induces caspase-dependent apoptosis, providing the basis for the apoptotic-process annotation. Reason: A pro-apoptotic role is supported but is overexpression-driven and context-dependent; secondary to the conserved mitophagy-receptor function. Supporting Evidence: PMID:11262395 its overexpression induces apoptosis that is specifically blocked by the caspase inhibitors, IAPs |
| GO:0005739 mitochondrion | NAS PMID:11262395 Bcl-rambo, a novel Bcl-2 homologue that induces apoptosis vi... | ACCEPT | Summary: The founding study localized Bcl-rambo to mitochondria. Reason: Directly supported core localization. Supporting Evidence: PMID:11262395 Bcl-rambo was localized to mitochondria |
| GO:0008656 cysteine-type endopeptidase activator activity involved in apoptotic process | NAS PMID:11262395 Bcl-rambo, a novel Bcl-2 homologue that induces apoptosis vi... | KEEP AS NON CORE | Summary: BCL2L13-induced apoptosis is caspase-dependent (blocked by caspase inhibitors/IAPs), and UniProt states it may promote caspase-3 activation; this caspase-activator annotation captures a contextual pro-apoptotic effect rather than a direct, conserved molecular function. Reason: The caspase-3 activation is indirect/context-dependent (overexpression-driven apoptosis) and is not the conserved core molecular function (mitophagy-receptor activity); retained as a non-core apoptosis-related annotation. Supporting Evidence: PMID:11262395 its overexpression induces apoptosis that is specifically blocked by the caspase inhibitors, IAPs file:human/BCL2L13/BCL2L13-uniprot.txt May promote the activation of caspase-3 and apoptosis. |
| GO:0016020 membrane | IDA PMID:11262395 Bcl-rambo, a novel Bcl-2 homologue that induces apoptosis vi... | MARK AS OVER ANNOTATED | Summary: Bcl-rambo's cell-death activity maps to its membrane-anchored C-terminal domain; generic membrane localization is correct but uninformative. Reason: Subsumed by the specific mitochondrial (outer) membrane localization. Supporting Evidence: PMID:11262395 the Bcl-rambo cell death activity was induced by its membrane-anchored C-terminal domain |
| GO:0140580 mitochondrion autophagosome adaptor activity | IDA PMID:26146385 Bcl-2-like protein 13 is a mammalian Atg32 homologue that me... | NEW | Summary: BCL2L13/Bcl2-L-13 is an outer-mitochondrial-membrane mitophagy receptor that binds LC3 through its WXXI/LIR motif and recruits autophagy machinery to mitochondria. Reason: The PN-guided review identified that the YAML's proposed "mitophagy receptor activity" request is already covered by GO:0140580. This existing MF should be added instead of requesting a new term. Supporting Evidence: PMID:26146385 Bcl2-L-13 binds to LC3 through the WXXI motif and induces mitochondrial fragmentation and mitophagy |
| GO:0000423 mitophagy | IMP PMID:26146385 Bcl-2-like protein 13 is a mammalian Atg32 homologue that me... | NEW | Summary: BCL2L13 promotes selective autophagy of mitochondria, and knockdown attenuates damage-induced mitochondrial fragmentation and mitophagy. Reason: The review already treats mitophagy as the core biological process, but the seeded existing_annotations lacked a manual recommendation for the BP term. This adds the existing GO process term with primary evidence. Supporting Evidence: PMID:26146385 Knockdown of Bcl2-L-13 attenuates mitochondrial damage-induced fragmentation and mitophagy |
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Download this section (compressed HTML)Q: In normal physiology, is BCL2L13's predominant role the Atg32-like mitophagy-receptor function, the pro-apoptotic function, or are these separable activities engaged in different cell types or stress conditions?
Suggested experts: Murakawa T, Otsu K
Q: Does BCL2L13-mediated mitochondrial fragmentation occur independently of the canonical DRP1 fission machinery, and how is the LIR-dependent LC3 binding regulated?
Suggested experts: Murakawa T, Otsu K
Q: Is BCL2L13's localization to ER-mitochondria contact sites (mitochondria-associated membranes) and its regulation of ER-mitochondria Ca2+ flux a distinct function from its mitophagy-receptor activity, or are the two mechanistically coupled?
Suggested experts: Amati F, Grepper D
Q: How is the choice between DRP1-independent fragmentation (Murakawa) and DNM1L/DRP1-Ser616-dependent fission (glioblastoma) determined, and which cellular contexts favor each, given the opposing tissue-dependent roles of BCL2L13 (pro-survival in GBM vs tumor-suppressive in renal cell carcinoma)?
Experiment: Compare wild-type BCL2L13 with LIR-motif point mutants for LC3/GABARAP co-immunoprecipitation and for the ability to induce mitochondrial fragmentation and mitophagy (mito-Keima/mito-QC flux) in BCL2L13-null cells, including under uncoupler-induced and starvation-induced conditions.
Hypothesis: BCL2L13 acts as an LIR-dependent mitophagy receptor that recruits LC3/GABARAP to mitochondria to drive their selective autophagy.
Type: structure-function rescue and mitophagy flux assay
Experiment: Use domain-deletion and point-mutant constructs (BH motifs, LIR motif, C-terminal insertion/TM) to dissociate caspase-3 activation/apoptosis from LC3-dependent mitophagy, measuring both readouts in parallel in defined cell models.
Hypothesis: The pro-apoptotic and mitophagy-receptor activities of BCL2L13 are mechanistically separable.
Type: domain dissection with parallel apoptosis and mitophagy readouts
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