API5

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005634 nucleus	IBA GO_REF:0000033	ACCEPT	Summary: API5 is predominantly nuclear as confirmed by multiple studies. The protein contains a nuclear localization signal (NLS) at residues 454-475 and localizes to the nucleus where it performs its anti-apoptotic scaffold functions [PMID:11075807]. Reason: Nuclear localization is well-established for API5. The IBA annotation is consistent with direct experimental evidence from PMID:11075807 showing nuclear localization, and UniProt confirms this with IDA evidence. The protein's functions in transcriptional regulation, caspase-2 inhibition, and Acinus binding all occur in the nucleus. Supporting Evidence: PMID:11075807 we have isolated a gene encoding a nuclear protein of 55 kDa, FIF (FGF-2-interacting-factor), which interacts specifically with FGF-2
GO:0003723 RNA binding	IBA GO_REF:0000033	ACCEPT	Summary: API5 has been implicated in mRNA export via TREX/eIF4E/CRM1 pathways and has been identified as part of the spliceosomal complex. High-throughput mRNA interactome studies have detected API5 as an mRNA-binding protein [file:human/API5/API5-deep-research-falcon.md]. Reason: The IBA annotation is supported by HDA evidence from mRNA interactome studies (PMID:22658674, PMID:22681889) and the protein's association with spliceosomal complexes. While not a primary catalytic function, RNA binding is consistent with API5's scaffold role in nuclear processes. Supporting Evidence: file:human/API5/API5-deep-research-falcon.md API5 participates in nuclear FGF-2 complexes and has been implicated in mRNA export (TREX/eIF4E/CRM1 pathways)
GO:0043066 negative regulation of apoptotic process	IBA GO_REF:0000033	ACCEPT	Summary: This is the core function of API5. The protein inhibits apoptosis through multiple specific mechanisms: (1) direct binding to caspase-2 CARD domain preventing activation, (2) binding and protecting Acinus from caspase-3 cleavage, and (3) suppressing E2F1-dependent apoptosis. The IBA annotation is strongly supported by extensive experimental literature [PMID:9307294, PMID:19387494]. Reason: Negative regulation of apoptosis is API5's defining function. This is supported by the original discovery paper [PMID:9307294] showing cells expressing AAC-11 survive serum withdrawal, and the Acinus protection study [PMID:19387494]. Supporting Evidence: PMID:9307294 BALB/c3T3 fibroblasts that were stably transfected with AAC-11 cDNA were viable in serum-free medium for up to 12 weeks PMID:19387494 We report here that AAC-11, a survival protein whose expression prevents apoptosis that occurs on deprivation of growth factors, physiologically binds to Acinus and prevents Acinus-mediated DNA fragmentation
GO:0005634 nucleus	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for nuclear localization based on automated methods. Consistent with extensive experimental evidence. Reason: Redundant with IBA and IDA annotations but correct. Nuclear localization is API5's primary location and is well-supported by experimental evidence. Supporting Evidence: PMID:11075807 we have isolated a gene encoding a nuclear protein of 55 kDa, FIF (FGF-2-interacting-factor)
GO:0005737 cytoplasm	IEA GO_REF:0000044	ACCEPT	Summary: API5 is predominantly nuclear but can also be cytoplasmic. UniProt notes "Mainly nuclear. Can also be cytoplasmic." Cytoplasmic localization is associated with stress-induced degradation via the ATR-FBXW2 pathway [file:human/API5/API5-deep-research-falcon.md]. Reason: While nucleus is the primary location, cytoplasmic localization is a real physiological state, particularly during stress responses when API5 is targeted for proteasomal degradation. Isoform 3 is specifically cytoplasmic. Supporting Evidence: file:human/API5/API5-deep-research-falcon.md DNA damage shifts API5 toward cytoplasmic degradation via ATR-FBXW2-proteasome, functionally coupling checkpoint activation to relief of API5-mediated apoptosis suppression
GO:0006915 apoptotic process	IEA GO_REF:0000043	MODIFY	Summary: This annotation from UniProtKB keyword mapping is too general. API5 specifically NEGATIVELY regulates apoptosis; it does not simply participate in the apoptotic process without direction. Reason: The term "apoptotic process" is ambiguous about direction. API5 is specifically an anti-apoptotic protein that inhibits multiple steps of the apoptotic cascade. The more accurate term is GO:0043066 (negative regulation of apoptotic process), which is already annotated with stronger evidence. Proposed replacements: negative regulation of apoptotic process Supporting Evidence: PMID:9307294 The corresponding native protein may function as a novel inhibitor of apoptosis
GO:0043066 negative regulation of apoptotic process	IEA GO_REF:0000117	ACCEPT	Summary: IEA annotation from ARBA machine learning models for negative regulation of apoptotic process. Consistent with the core function of API5. Reason: Correct annotation, redundant with IBA, TAS, ISS, NAS, and IMP annotations for the same term. This is API5's core function. Supporting Evidence: PMID:9307294 a cDNA whose expression supports cell viability after withdrawal of growth factors
GO:0005515 protein binding	IPI PMID:19387494 The antiapoptotic protein AAC-11 interacts with and regulate...	MODIFY	Summary: This annotation captures the interaction between API5 (AAC-11) and Acinus (ACIN1). The interaction is functionally significant as API5 binding protects Acinus from caspase-3 cleavage and prevents Acinus-mediated DNA fragmentation. Reason: While the protein binding annotation is technically correct, it is uninformative. The specific interaction with Acinus (a chromatin condensation/DNA fragmentation factor) is a core mechanistic function of API5. A more specific term describing this scaffold/protective binding function would be more informative, but GO may lack an appropriate term. The key point is this represents meaningful functional binding, not generic protein binding. Proposed replacements: negative regulation of apoptotic process Supporting Evidence: PMID:19387494 AAC-11 was able to protect Acinus from caspase-3 cleavage in vivo and in vitro, thus interfering with its biological function
GO:0005515 protein binding	IPI PMID:30021884 Histone Interaction Landscapes Visualized by Crosslinking Ma...	KEEP AS NON CORE	Summary: This annotation is from a crosslinking mass spectrometry study detecting API5 interaction with DDX39B (a DEAD-box RNA helicase involved in mRNA export). This interaction may relate to API5's reported role in mRNA export pathways. Reason: While the interaction with DDX39B is from high-quality crosslinking MS data, it represents a secondary function related to RNA biology rather than API5's core anti-apoptotic role. The "protein binding" term is uninformative. Supporting Evidence: file:human/API5/API5-deep-research-falcon.md API5 participates in nuclear FGF-2 complexes and has been implicated in mRNA export (TREX/eIF4E/CRM1 pathways) PMID:30021884 Epub 2018 Jul 18. Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry in Intact Cell Nuclei.
GO:0005515 protein binding	IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce...	KEEP AS NON CORE	Summary: This annotation is from the OpenCell project (endogenous tagging for cellular organization cartography) detecting API5 interaction with DDX39B. Reason: Redundant with PMID:30021884 annotation for DDX39B interaction. High-throughput interaction data; the "protein binding" term is too general to be informative about API5's specific functions. Supporting Evidence: file:human/API5/API5-deep-research-falcon.md API5 participates in nuclear FGF-2 complexes and has been implicated in mRNA export (TREX/eIF4E/CRM1 pathways) PMID:35271311 2022 Mar 11. OpenCell: Endogenous tagging for the cartography of human cellular organization.
GO:0005681 spliceosomal complex	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA annotation based on transfer from mouse ortholog (O35841). Mouse Api5 was found in spliceosomal complexes in the large-scale nuclear sub-compartment study. Reason: While API5 may associate with splicing machinery, this is likely secondary to its core anti-apoptotic functions. The association may relate to API5's RNA binding capacity and nuclear scaffold role rather than direct splicing function. Supporting Evidence: PMID:11555636 The most common discrete localizations detected are at the nucleolus and the splicing speckles
GO:0016607 nuclear speck	IDA GO_REF:0000052	ACCEPT	Summary: Nuclear speck localization from HPA immunofluorescence data. Nuclear speckles are enriched in splicing factors, consistent with API5's association with spliceosomal complexes and RNA binding. Reason: IDA evidence from HPA immunofluorescence. Nuclear speck localization is consistent with API5's nuclear scaffold role and association with RNA processing machinery. This is a reasonable sub-nuclear localization annotation. Supporting Evidence: PMID:11555636 The most common discrete localizations detected are at the nucleolus and the splicing speckles
GO:0016020 membrane	HDA PMID:19946888 Defining the membrane proteome of NK cells.	MARK AS OVER ANNOTATED	Summary: This annotation is from a study defining the membrane proteome of NK cells. API5 is not a transmembrane protein and is predominantly nuclear. This may represent non-specific association or a minor localization. Reason: API5 is a nuclear scaffold protein without transmembrane domains. While it may have been detected in membrane fractions in the NK cell proteomics study, this is likely not a physiologically relevant localization for its core functions. The HDA evidence from a proteomics study may reflect contamination or transient association. Supporting Evidence: file:human/API5/API5-deep-research-falcon.md Basal state: predominantly nuclear, chromatin-associated, with acetylation at K251 stabilizing the protein and supporting nuclear functions PMID:19946888 Defining the membrane proteome of NK cells.
GO:0003723 RNA binding	HDA PMID:22658674 Insights into RNA biology from an atlas of mammalian mRNA-bi...	ACCEPT	Summary: RNA binding detected in the mRNA-bound proteome atlas study by Castello et al. This supports API5's association with mRNA processing/export pathways. Reason: HDA evidence from systematic mRNA interactome capture. Consistent with API5's reported roles in mRNA export and association with spliceosomal complexes. While not a core function, RNA binding is a validated molecular function. Supporting Evidence: file:human/API5/API5-deep-research-falcon.md API5 participates in nuclear FGF-2 complexes and has been implicated in mRNA export (TREX/eIF4E/CRM1 pathways) PMID:22658674 May 31. Insights into RNA biology from an atlas of mammalian mRNA-binding proteins.
GO:0003723 RNA binding	HDA PMID:22681889 The mRNA-bound proteome and its global occupancy profile on ...	ACCEPT	Summary: RNA binding detected in the Baltz et al. mRNA-bound proteome study. Redundant with PMID:22658674 annotation. Reason: Independent HDA evidence supporting RNA binding function. Consistent with other annotations for this molecular function. Supporting Evidence: file:human/API5/API5-deep-research-falcon.md API5 participates in nuclear FGF-2 complexes and has been implicated in mRNA export (TREX/eIF4E/CRM1 pathways) PMID:22681889 The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts.
GO:0005634 nucleus	IDA PMID:11075807 FIF [fibroblast growth factor-2 (FGF-2)-interacting-factor],...	ACCEPT	Summary: Direct experimental evidence for nuclear localization from the FIF discovery paper. This is the primary localization study for API5. Reason: IDA evidence from the study that characterized FIF (API5) as an FGF-2 interacting factor. Nuclear localization is fundamental to API5's functions in apoptosis regulation and transcriptional control. Supporting Evidence: PMID:11075807 we have isolated a gene encoding a nuclear protein of 55 kDa, FIF (FGF-2-interacting-factor), which interacts specifically with FGF-2
GO:0043066 negative regulation of apoptotic process	TAS PMID:9307294 AAC-11, a novel cDNA that inhibits apoptosis after growth fa...	ACCEPT	Summary: TAS annotation based on the original AAC-11 discovery paper by Tewari et al. This seminal paper identified API5 through functional expression cloning as a gene that prevents apoptosis after growth factor withdrawal. Reason: The original discovery paper provides strong evidence for anti-apoptotic function. Cells expressing AAC-11 survived serum-free conditions for up to 12 weeks. The leucine zipper domain was shown to be essential for this protective function. Supporting Evidence: PMID:9307294 BALB/c3T3 fibroblasts that were stably transfected with AAC-11 cDNA were viable in serum-free medium for up to 12 weeks
GO:0043066 negative regulation of apoptotic process	ISS PMID:9307294 AAC-11, a novel cDNA that inhibits apoptosis after growth fa...	ACCEPT	Summary: ISS annotation based on sequence similarity to mouse Api5, with reference to the original AAC-11 paper showing conservation of anti-apoptotic function. Reason: API5 family is conserved across species and the anti-apoptotic function is preserved. The original paper noted "strong species conservation" of the AAC-11 gene. Supporting Evidence: PMID:9307294 The AAC-11 gene shows strong species conservation and is ubiquitously expressed in embryonic and adult tissues
GO:0005681 spliceosomal complex	ISS PMID:11555636 Large-scale identification of mammalian proteins localized t...	KEEP AS NON CORE	Summary: ISS annotation based on mouse Api5 localization to splicing speckles in the large-scale nuclear sub-compartment identification study. Reason: Association with spliceosomal complex/splicing speckles is supported by independent localization data but represents a secondary function or localization rather than API5's core anti-apoptotic role. Supporting Evidence: PMID:11555636 The most common discrete localizations detected are at the nucleolus and the splicing speckles
GO:0005737 cytoplasm	NAS PMID:11075807 FIF [fibroblast growth factor-2 (FGF-2)-interacting-factor],...	ACCEPT	Summary: NAS annotation for cytoplasmic localization. While API5 is predominantly nuclear, cytoplasmic localization exists, especially for isoform 3 and during stress-induced degradation. Reason: The FIF paper identified multiple isoforms with different localizations. While isoform 3 is specifically cytoplasmic, the full-length protein can shuttle to cytoplasm under certain conditions. Supporting Evidence: PMID:11075807 In contrast to the full-length FIF protein, several deletion constructs were able to transactivate a lac-Z reporter gene
GO:0017134 fibroblast growth factor binding	IPI PMID:11075807 FIF [fibroblast growth factor-2 (FGF-2)-interacting-factor],...	ACCEPT	Summary: IPI annotation for FGF2 binding. The FIF (API5) protein was originally identified as an FGF-2 interacting factor through yeast two-hybrid screening. The interaction is specific for FGF-2 over FGF-1, FGF-3, and FGF-6. Reason: FGF2 binding is well-documented and specific. Two regions of API5 (N-terminal aa 96-107 and C-terminal aa 274-311) are required for FGF2 binding. This interaction may contribute to API5's role in growth factor signaling and survival pathways. Supporting Evidence: PMID:11075807 The region spanning these repeats is, together with a region located in the N-terminal part of the FIF protein, implicated in the binding to FGF-2
GO:0043066 negative regulation of apoptotic process	NAS PMID:10780674 AAC-11 overexpression induces invasion and protects cervical...	ACCEPT	Summary: NAS annotation based on cervical cancer study showing AAC-11 overexpression protects cells from apoptosis. Cells survived serum-free conditions longer when expressing AAC-11. Reason: The study provides additional evidence for anti-apoptotic function in cancer cell context. AAC-11 transfected cells showed extended survival under serum-free conditions. Supporting Evidence: PMID:10780674 Approximately 50% of the AAC-11 transfected cells in serum-free medium died after 2 weeks, compared to 1 week for vector alone or wild-type cells
GO:0043066 negative regulation of apoptotic process	IMP PMID:11075807 FIF [fibroblast growth factor-2 (FGF-2)-interacting-factor],...	ACCEPT	Summary: IMP annotation from the FIF paper showing anti-apoptotic function through mutant phenotype analysis. The C-terminal portion of FIF was shown to have antiapoptotic properties. Reason: IMP evidence from functional studies. The paper discusses that the C-terminal part exhibits antiapoptotic properties, supporting the anti-apoptotic function of API5. Supporting Evidence: PMID:11075807 the COOH-terminal part, but not the full-length FIF protein, has previously been shown to exhibit antiapoptotic properties
GO:0043027 cysteine-type endopeptidase inhibitor activity involved in apoptotic process	IDA PMID:28336776 Apoptosis inhibitor 5 is an endogenous inhibitor of caspase-...	NEW	Summary: API5 directly binds the CARD domain of caspase-2, preventing its dimerization and activation. This is a key mechanism of API5's anti-apoptotic function distinct from Acinus protection [file:human/API5/API5-deep-research-falcon.md]. Reason: The deep research review identifies direct caspase-2 inhibition as a major mechanism of API5 anti-apoptotic function (Imre et al., EMBO Reports 2017, PMID:28336776). This specific molecular function is not captured by the general "negative regulation of apoptotic process" annotations. Supporting Evidence: file:human/API5/API5-deep-research-falcon.md API5 directly binds the CARD of caspase-2, preventing its dimerization/activation; recombinant API5 inhibits full-length but not processed caspase-2 PMID:28336776 Apoptosis inhibitor 5 is an endogenous inhibitor of caspase-2.

Gene Description

Existing Annotations Review

Core Functions

API5/FIF specifically binds FGF2 through two regions (N-terminal aa 96-107 and C-terminal aa 274-311). This interaction may contribute to growth factor signaling and survival pathway activation.

API5 localizes to nucleus via NLS (aa 454-475) where it performs scaffold functions through HEAT/ARM-like helical repeats, leucine zipper domain, and LxxLL motif. Associates with nuclear speckles and spliceosomal complexes.

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