{"gene":"AKAP8L","run_date":"2026-06-09T22:02:43","timeline":{"discoveries":[{"year":2000,"finding":"HAP95 (AKAP8L) was identified as a novel nuclear protein that specifically binds to the carboxyl terminus (nuclear transport domain) of RNA helicase A (RHA). HAP95 shuttles between nucleus and cytoplasm, and overexpression significantly increases CTE-dependent gene expression without affecting general gene expression or HIV-1 Rev/RRE-mediated expression.","method":"Protein–protein interaction (binding to RHA C-terminus), nuclear-cytoplasmic shuttling assays, reporter gene expression assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding mapped, functional shuttling and CTE transactivation shown, single lab with multiple orthogonal methods","pmids":["10748171"],"is_preprint":false},{"year":2001,"finding":"Truncation and deletion mapping of HAP95 (AKAP8L) defined functional domains: a domain for RHA binding, a novel nuclear export signal, and a nuclear localization domain. Both the RHA-binding and nuclear localization domains are required for CTE activation. HAP95 synergizes with RHA to promote nuclear export of unspliced mRNA.","method":"Truncation/deletion mutagenesis, CTE reporter assays, nuclear export assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mapping by mutagenesis, functional validation of each domain, single lab","pmids":["11402034"],"is_preprint":false},{"year":2000,"finding":"AKAP8L (NAKAP95) was identified as a nuclear protein encoded on chromosome 19p13.11-p13.12, tandemly arranged ~250 bp from AKAP95 (AKAP8). It shares ~40% similarity with AKAP95 including nuclear localization signal and two C2H2 zinc finger motifs, but lacks the RII (PKA regulatory subunit) binding motif conserved in AKAP95.","method":"cDNA cloning, chromosomal mapping (hybrid cell panels, radiation hybrid panel), RT-PCR, sequence alignment","journal":"Journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct cloning and chromosomal mapping with sequence comparison; absence of RII-binding motif inferred from sequence, not biochemically tested","pmids":["10697960"],"is_preprint":false},{"year":2008,"finding":"HAP95 (AKAP8L) was identified as an RNF43-interacting protein by yeast two-hybrid screening, and the interaction was confirmed by co-immunoprecipitation in intact cells. HAP95 is ubiquitylated and subject to proteasome-dependent degradation; however, HAP95 is not a substrate of RNF43 ubiquitin ligase activity.","method":"Yeast two-hybrid screening, co-immunoprecipitation, proteasome inhibitor treatment (MG132), ubiquitylation assay","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction confirmed by co-IP, negative result on RNF43 substrate status explicitly tested with proteasome inhibitor, single lab","pmids":["18313049"],"is_preprint":false},{"year":2014,"finding":"HAP95 (AKAP8L) associates with the reverse transcriptase region of HIV-1 Pol protein. siRNA-mediated knockdown of HAP95 in HIV-1-producing cells reduces tRNALys3 annealing to viral RNA, an effect further worsened by co-knockdown of RHA, indicating cooperative function. In vitro biochemical assay with purified GST-HAP95 shows HAP95 inhibits RHA helicase activity, suggesting HAP95 transiently blocks RHA to protect annealed tRNALys3 from displacement.","method":"siRNA knockdown, co-immunoprecipitation (Pol association), in vitro biochemical assay with purified GST-HAP95","journal":"Retrovirology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro assay with purified protein plus cellular knockdown, single lab, functional readout of tRNA annealing","pmids":["25034436"],"is_preprint":false},{"year":2018,"finding":"AKAP8L, a homologue of AKAP8, interacts with core subunits of H3K4 histone methyltransferase (HMT) complexes (e.g., DPY30), suggesting a role as a potential regulator of these complexes. This was shown in the context of characterizing AKAP8-DPY30 interactions.","method":"Co-immunoprecipitation (interaction with H3K4 HMT core subunits)","journal":"The FEBS journal","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP reported as supporting evidence in a paper primarily about AKAP8; minimal mechanistic detail for AKAP8L specifically","pmids":["29288530"],"is_preprint":false},{"year":2020,"finding":"AKAP8L was identified as a novel mTORC1-interacting protein. The N-terminal region of AKAP8L binds mTORC1 in the cytoplasm. Loss of AKAP8L decreases mTORC1-mediated translation, cell growth, and cell proliferation. AKAP8L can anchor PKA through its regulatory subunit Iα. Reintroduction of full-length AKAP8L rescued mTORC1-regulated processes, whereas reintroduction lacking the N-terminal mTORC1-binding region did not.","method":"Biochemical assays (co-immunoprecipitation, pulldown), domain deletion/rescue experiments, cell growth/proliferation assays, translation assays, loss-of-function studies","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — interaction domain mapped by deletion mutants with rescue experiments, multiple orthogonal functional readouts (translation, growth, proliferation), single lab but rigorous design","pmids":["32312749"],"is_preprint":false},{"year":2020,"finding":"Knockdown of AKAP8L in primary human hematopoietic stem cells suppressed commitment to the erythroid lineage and cell proliferation, and delayed differentiation from colony-forming unit-erythroid (CFU-E) to the proerythroblast (ProE) stage.","method":"siRNA/shRNA knockdown, cell differentiation assays, apoptosis monitoring, single-cell transcriptomics-guided functional validation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct loss-of-function with specific differentiation stage phenotype, single lab, no molecular mechanism identified beyond the cellular phenotype","pmids":["32457162"],"is_preprint":false},{"year":2022,"finding":"AKAP8L interacts with IGF2BP1 protein and SCD1 mRNA, stabilizing SCD1 mRNA in an IGF2BP1-dependent manner in gastric cancer cells. This mechanism promotes cancer cell stemness and chemoresistance to oxaliplatin.","method":"Co-immunoprecipitation (AKAP8L–IGF2BP1), RNA immunoprecipitation (AKAP8L–SCD1 mRNA), mRNA stability assays, overexpression and knockdown in vitro and in vivo","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal interactions shown, mRNA stability functionally validated, in vivo and in vitro experiments, single lab","pmids":["36522343"],"is_preprint":false},{"year":2024,"finding":"In high-glucose-treated microglia, AKAP8L is upregulated and physically interacts with mTORC1 (shown by co-immunoprecipitation and proximity ligation assay). AKAP8L knockdown enhanced autophagic flux, reduced mTORC1 signaling, reduced neuroinflammation and pyroptosis, and improved cognitive function in STZ-diabetic mice, indicating AKAP8L acts upstream of mTORC1 to inhibit autophagy and promote neuroinflammation.","method":"Co-immunoprecipitation, proximity ligation assay, siRNA knockdown, rapamycin treatment, Morris water maze, autophagic flux assays, proteomics","journal":"Journal of neuroinflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — interaction confirmed by two methods (co-IP + PLA), functional in vivo rescue with knockdown and pharmacological comparator, single lab","pmids":["39033121"],"is_preprint":false},{"year":2018,"finding":"SARNAclust analysis of eCLIP data identified novel RNA sequence/structure binding motifs for AKAP8L as an RNA-binding protein, indicating AKAP8L has sequence/structure-specific RNA binding activity.","method":"eCLIP data analysis, computational motif discovery (SARNAclust)","journal":"PLoS computational biology","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational analysis of existing eCLIP data, no direct biochemical validation of AKAP8L-specific motif","pmids":["29596423"],"is_preprint":false},{"year":2023,"finding":"A PTEN–AKAP8L interaction was identified in human iPSC-derived excitatory neurons, and this interaction was shown to influence neuronal growth in the context of an ASD protein-protein interaction network.","method":"Protein-protein interaction network (AP-MS in human neurons), functional neuronal growth assay","journal":"Cell genomics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — interaction identified in a network-scale study with some functional follow-up on neuronal growth; specific mechanistic details for AKAP8L are limited","pmids":["36950384"],"is_preprint":false}],"current_model":"AKAP8L (HAP95/NAKAP95) is a nuclear/shuttling protein that binds RNA helicase A (RHA) via its C-terminal transport domain to facilitate CTE-mediated nuclear export of unspliced retroviral mRNA; it anchors PKA regulatory subunit Iα; its N-terminal region directly binds mTORC1 in the cytoplasm to promote translation, cell growth, and proliferation; it stabilizes SCD1 mRNA through interaction with IGF2BP1; and in microglia it interacts with mTORC1 to suppress autophagy and promote neuroinflammation, while also playing a role in erythroid lineage commitment in hematopoietic stem cells."},"narrative":{"mechanistic_narrative":"AKAP8L (HAP95/NAKAP95) is a nucleocytoplasmic shuttling protein that participates in both nuclear RNA export and cytoplasmic growth-signaling control [PMID:10748171, PMID:32312749]. In the nucleus it binds the C-terminal nuclear transport domain of RNA helicase A (RHA) and, through its own RHA-binding and nuclear localization domains plus a novel nuclear export signal, synergizes with RHA to drive CTE-mediated nuclear export of unspliced mRNA [PMID:10748171, PMID:11402034]. This RHA partnership is co-opted during HIV-1 replication, where AKAP8L associates with the reverse transcriptase region of Pol and inhibits RHA helicase activity in vitro to protect annealed tRNA-Lys3 on viral RNA [PMID:25034436]. In the cytoplasm, its N-terminal region directly binds mTORC1 to promote mTORC1-mediated translation, cell growth, and proliferation, with rescue requiring the intact N-terminal mTORC1-binding region [PMID:32312749]; in high-glucose-treated microglia this same interaction acts upstream of mTORC1 to suppress autophagy and promote neuroinflammation [PMID:39033121]. AKAP8L additionally stabilizes SCD1 mRNA in an IGF2BP1-dependent manner to support cancer cell stemness and chemoresistance [PMID:36522343], and supports erythroid lineage commitment of hematopoietic stem cells [PMID:32457162]. Although it is a structural homolog of the A-kinase anchoring protein AKAP8 and can anchor the PKA regulatory subunit Iα, it lacks the canonical RII-binding motif of AKAP8 [PMID:10697960, PMID:32312749].","teleology":[{"year":2000,"claim":"Established AKAP8L as a nuclear shuttling protein that acts on retroviral RNA export by binding RNA helicase A, defining its first molecular function.","evidence":"RHA C-terminus binding, shuttling assays, and CTE reporter gene assays","pmids":["10748171"],"confidence":"Medium","gaps":["Binding region on AKAP8L not yet mapped","Specificity for CTE versus Rev/RRE export explained only at the phenotypic level"]},{"year":2000,"claim":"Defined AKAP8L's genomic and structural relationship to AKAP8, showing it shares NLS and zinc-finger motifs but lacks the RII-binding motif, distinguishing it from a canonical AKAP.","evidence":"cDNA cloning, chromosomal mapping, and sequence alignment","pmids":["10697960"],"confidence":"Medium","gaps":["Absence of RII binding inferred from sequence, not biochemically tested","Functional consequence of zinc-finger motifs unknown"]},{"year":2001,"claim":"Mapped the domains underlying export function, showing both RHA-binding and nuclear localization domains are required for CTE activation and that AKAP8L synergizes with RHA for unspliced mRNA export.","evidence":"Truncation/deletion mutagenesis with CTE reporter and nuclear export assays","pmids":["11402034"],"confidence":"Medium","gaps":["Mechanism of synergy with RHA at the molecular level unresolved","Endogenous cellular RNA substrates not identified"]},{"year":2008,"claim":"Identified AKAP8L as an RNF43-interacting protein subject to proteasomal turnover, while excluding RNF43 as its ubiquitin ligase.","evidence":"Yeast two-hybrid, co-IP, MG132 treatment, and ubiquitylation assay","pmids":["18313049"],"confidence":"Medium","gaps":["The responsible E3 ligase remains unidentified","Functional significance of the RNF43 interaction unknown"]},{"year":2014,"claim":"Extended the RHA partnership to a viral mechanism, showing AKAP8L associates with HIV-1 Pol and inhibits RHA helicase activity to protect tRNA-Lys3 annealing.","evidence":"siRNA knockdown, Pol co-IP, and in vitro helicase assay with purified GST-AKAP8L","pmids":["25034436"],"confidence":"Medium","gaps":["Single lab; helicase inhibition shown in vitro only","Whether this role applies to host RNAs not addressed"]},{"year":2020,"claim":"Discovered a distinct cytoplasmic role: the N-terminal region binds mTORC1 to drive translation, growth, and proliferation, with domain-specific rescue establishing causality.","evidence":"Co-IP, pulldown, deletion/rescue, and translation/growth/proliferation assays","pmids":["32312749"],"confidence":"High","gaps":["Direct mTORC1 subunit contacted not pinpointed","How nuclear export and mTORC1 roles are coordinated unknown"]},{"year":2020,"claim":"Linked AKAP8L to a developmental process, showing it is required for erythroid lineage commitment and proliferation of hematopoietic stem cells.","evidence":"Knockdown with differentiation/apoptosis assays guided by single-cell transcriptomics","pmids":["32457162"],"confidence":"Medium","gaps":["No molecular mechanism beyond the cellular phenotype","Connection to its mTORC1 or RNA roles untested"]},{"year":2022,"claim":"Defined an RNA-stabilizing function through IGF2BP1, showing AKAP8L stabilizes SCD1 mRNA to promote cancer stemness and chemoresistance.","evidence":"Co-IP, RNA-IP, mRNA stability assays, and in vitro/in vivo perturbation in gastric cancer cells","pmids":["36522343"],"confidence":"Medium","gaps":["Generality of the IGF2BP1 partnership beyond SCD1 unknown","Relationship to nuclear RNA export role unclear"]},{"year":2024,"claim":"Connected the mTORC1 interaction to a disease-relevant pathway, showing AKAP8L acts upstream of mTORC1 in microglia to suppress autophagy and drive neuroinflammation.","evidence":"Co-IP, PLA, knockdown, rapamycin comparator, and behavioral/autophagy assays in STZ-diabetic mice","pmids":["39033121"],"confidence":"Medium","gaps":["Mechanism by which AKAP8L activates mTORC1 not defined","Single lab/disease model"]},{"year":null,"claim":"How AKAP8L coordinates its nuclear RNA-export functions with its cytoplasmic mTORC1-anchoring and PKA-anchoring roles, and what governs its compartment-specific partner selection, remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unifying model linking RNA-binding and growth-signaling functions","Structural basis of mTORC1 and RHA contacts not determined","PKA-anchoring role not functionally dissected"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[0,8]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[6,9]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6,9]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0,1]}],"complexes":[],"partners":["DHX9","MTOR","IGF2BP1","RNF43","PRKAR1A","PTEN"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9ULX6","full_name":"A-kinase anchor protein 8-like","aliases":["Helicase A-binding protein 95","HAP95","Homologous to AKAP95 protein","HA95","Neighbor of A-kinase-anchoring protein 95","Neighbor of AKAP95"],"length_aa":646,"mass_kda":71.6,"function":"Could play a role in constitutive transport element (CTE)-mediated gene expression by association with DHX9. Increases CTE-dependent nuclear unspliced mRNA export (PubMed:10748171, PubMed:11402034). Proposed to target PRKACA to the nucleus but does not seem to be implicated in the binding of regulatory subunit II of PKA (PubMed:10761695, PubMed:11884601). May be involved in nuclear envelope breakdown and chromatin condensation. May be involved in anchoring nuclear membranes to chromatin in interphase and in releasing membranes from chromating at mitosis (PubMed:11034899). May regulate the initiation phase of DNA replication when associated with TMPO isoform Beta (PubMed:12538639). Required for cell cycle G2/M transition and histone deacetylation during mitosis. In mitotic cells recruits HDAC3 to the vicinity of chromatin leading to deacetylation and subsequent phosphorylation at 'Ser-10' of histone H3; in this function seems to act redundantly with AKAP8 (PubMed:16980585). May be involved in regulation of pre-mRNA splicing (PubMed:17594903) (Microbial infection) In case of EBV infection, may target PRKACA to EBNA-LP-containing nuclear sites to modulate transcription from specific promoters (Microbial infection) Can synergize with DHX9 to activate the CTE-mediated gene expression of type D retroviruses (Microbial infection) In case of HIV-1 infection, involved in the DHX9-promoted annealing of host tRNA(Lys3) to viral genomic RNA as a primer in reverse transcription; in vitro negatively regulates DHX9 annealing activity","subcellular_location":"Nucleus; Nucleus matrix; Nucleus speckle; Nucleus, PML body; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9ULX6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/AKAP8L","classification":"Not Classified","n_dependent_lines":22,"n_total_lines":1208,"dependency_fraction":0.018211920529801324},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000011243","cell_line_id":"CID001543","localizations":[{"compartment":"chromatin","grade":3},{"compartment":"nuclear_punctae","grade":2}],"interactors":[{"gene":"HSPD1","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"DDX21","stoichiometry":0.2},{"gene":"DNAJB6","stoichiometry":0.2},{"gene":"DNAJC7","stoichiometry":0.2},{"gene":"SNRPC","stoichiometry":0.2},{"gene":"SSRP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID001543","total_profiled":1310},"omim":[{"mim_id":"612941","title":"PRE-mRNA-PROCESSING FACTOR 40 HOMOLOG A; PRPF40A","url":"https://www.omim.org/entry/612941"},{"mim_id":"612482","title":"RING FINGER PROTEIN 43; RNF43","url":"https://www.omim.org/entry/612482"},{"mim_id":"609475","title":"A-KINASE ANCHOR PROTEIN 8-LIKE PROTEIN; AKAP8L","url":"https://www.omim.org/entry/609475"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear speckles","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/AKAP8L"},"hgnc":{"alias_symbol":["NAKAP95","HAP95"],"prev_symbol":[]},"alphafold":{"accession":"Q9ULX6","domains":[{"cath_id":"-","chopping":"365-559","consensus_level":"medium","plddt":84.6029,"start":365,"end":559}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9ULX6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9ULX6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9ULX6-F1-predicted_aligned_error_v6.png","plddt_mean":54.47},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=AKAP8L","jax_strain_url":"https://www.jax.org/strain/search?query=AKAP8L"},"sequence":{"accession":"Q9ULX6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9ULX6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9ULX6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9ULX6"}},"corpus_meta":[{"pmid":"23633038","id":"PMC_23633038","title":"Ginseng saponin metabolite 20(S)-protopanaxadiol inhibits tumor growth by targeting multiple cancer signaling pathways.","date":"2013","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/23633038","citation_count":66,"is_preprint":false},{"pmid":"36528612","id":"PMC_36528612","title":"Mutations in SARS-CoV-2 structural proteins: a global analysis.","date":"2022","source":"Virology journal","url":"https://pubmed.ncbi.nlm.nih.gov/36528612","citation_count":58,"is_preprint":false},{"pmid":"32457162","id":"PMC_32457162","title":"Putative regulators for the continuum of erythroid differentiation revealed by single-cell transcriptome of human BM and UCB cells.","date":"2020","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/32457162","citation_count":52,"is_preprint":false},{"pmid":"18313049","id":"PMC_18313049","title":"A cancer-associated RING finger protein, RNF43, is a ubiquitin ligase that interacts with a nuclear protein, HAP95.","date":"2008","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/18313049","citation_count":46,"is_preprint":false},{"pmid":"10748171","id":"PMC_10748171","title":"A novel shuttle protein binds to RNA helicase A and activates the retroviral constitutive transport element.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10748171","citation_count":39,"is_preprint":false},{"pmid":"36950384","id":"PMC_36950384","title":"Protein interaction studies in human induced neurons indicate convergent biology underlying autism spectrum disorders.","date":"2023","source":"Cell genomics","url":"https://pubmed.ncbi.nlm.nih.gov/36950384","citation_count":39,"is_preprint":false},{"pmid":"11402034","id":"PMC_11402034","title":"Mapping the functional domains of HAP95, a protein that binds RNA helicase A and activates the constitutive transport element of type D retroviruses.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11402034","citation_count":23,"is_preprint":false},{"pmid":"24011924","id":"PMC_24011924","title":"High glucose-induced proteome alterations in hepatocytes and its possible relevance to diabetic liver disease.","date":"2013","source":"The Journal of nutritional biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24011924","citation_count":23,"is_preprint":false},{"pmid":"32312749","id":"PMC_32312749","title":"A-kinase anchoring protein 8L interacts with mTORC1 and promotes cell growth.","date":"2020","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32312749","citation_count":20,"is_preprint":false},{"pmid":"36522343","id":"PMC_36522343","title":"AKAP8L enhances the stemness and chemoresistance of gastric cancer cells by stabilizing SCD1 mRNA.","date":"2022","source":"Cell death & 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HAP95 shuttles between nucleus and cytoplasm, and overexpression significantly increases CTE-dependent gene expression without affecting general gene expression or HIV-1 Rev/RRE-mediated expression.\",\n      \"method\": \"Protein–protein interaction (binding to RHA C-terminus), nuclear-cytoplasmic shuttling assays, reporter gene expression assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding mapped, functional shuttling and CTE transactivation shown, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"10748171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Truncation and deletion mapping of HAP95 (AKAP8L) defined functional domains: a domain for RHA binding, a novel nuclear export signal, and a nuclear localization domain. Both the RHA-binding and nuclear localization domains are required for CTE activation. HAP95 synergizes with RHA to promote nuclear export of unspliced mRNA.\",\n      \"method\": \"Truncation/deletion mutagenesis, CTE reporter assays, nuclear export assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mapping by mutagenesis, functional validation of each domain, single lab\",\n      \"pmids\": [\"11402034\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"AKAP8L (NAKAP95) was identified as a nuclear protein encoded on chromosome 19p13.11-p13.12, tandemly arranged ~250 bp from AKAP95 (AKAP8). It shares ~40% similarity with AKAP95 including nuclear localization signal and two C2H2 zinc finger motifs, but lacks the RII (PKA regulatory subunit) binding motif conserved in AKAP95.\",\n      \"method\": \"cDNA cloning, chromosomal mapping (hybrid cell panels, radiation hybrid panel), RT-PCR, sequence alignment\",\n      \"journal\": \"Journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct cloning and chromosomal mapping with sequence comparison; absence of RII-binding motif inferred from sequence, not biochemically tested\",\n      \"pmids\": [\"10697960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"HAP95 (AKAP8L) was identified as an RNF43-interacting protein by yeast two-hybrid screening, and the interaction was confirmed by co-immunoprecipitation in intact cells. HAP95 is ubiquitylated and subject to proteasome-dependent degradation; however, HAP95 is not a substrate of RNF43 ubiquitin ligase activity.\",\n      \"method\": \"Yeast two-hybrid screening, co-immunoprecipitation, proteasome inhibitor treatment (MG132), ubiquitylation assay\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction confirmed by co-IP, negative result on RNF43 substrate status explicitly tested with proteasome inhibitor, single lab\",\n      \"pmids\": [\"18313049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HAP95 (AKAP8L) associates with the reverse transcriptase region of HIV-1 Pol protein. siRNA-mediated knockdown of HAP95 in HIV-1-producing cells reduces tRNALys3 annealing to viral RNA, an effect further worsened by co-knockdown of RHA, indicating cooperative function. In vitro biochemical assay with purified GST-HAP95 shows HAP95 inhibits RHA helicase activity, suggesting HAP95 transiently blocks RHA to protect annealed tRNALys3 from displacement.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation (Pol association), in vitro biochemical assay with purified GST-HAP95\",\n      \"journal\": \"Retrovirology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro assay with purified protein plus cellular knockdown, single lab, functional readout of tRNA annealing\",\n      \"pmids\": [\"25034436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"AKAP8L, a homologue of AKAP8, interacts with core subunits of H3K4 histone methyltransferase (HMT) complexes (e.g., DPY30), suggesting a role as a potential regulator of these complexes. This was shown in the context of characterizing AKAP8-DPY30 interactions.\",\n      \"method\": \"Co-immunoprecipitation (interaction with H3K4 HMT core subunits)\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP reported as supporting evidence in a paper primarily about AKAP8; minimal mechanistic detail for AKAP8L specifically\",\n      \"pmids\": [\"29288530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"AKAP8L was identified as a novel mTORC1-interacting protein. The N-terminal region of AKAP8L binds mTORC1 in the cytoplasm. Loss of AKAP8L decreases mTORC1-mediated translation, cell growth, and cell proliferation. AKAP8L can anchor PKA through its regulatory subunit Iα. Reintroduction of full-length AKAP8L rescued mTORC1-regulated processes, whereas reintroduction lacking the N-terminal mTORC1-binding region did not.\",\n      \"method\": \"Biochemical assays (co-immunoprecipitation, pulldown), domain deletion/rescue experiments, cell growth/proliferation assays, translation assays, loss-of-function studies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — interaction domain mapped by deletion mutants with rescue experiments, multiple orthogonal functional readouts (translation, growth, proliferation), single lab but rigorous design\",\n      \"pmids\": [\"32312749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Knockdown of AKAP8L in primary human hematopoietic stem cells suppressed commitment to the erythroid lineage and cell proliferation, and delayed differentiation from colony-forming unit-erythroid (CFU-E) to the proerythroblast (ProE) stage.\",\n      \"method\": \"siRNA/shRNA knockdown, cell differentiation assays, apoptosis monitoring, single-cell transcriptomics-guided functional validation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct loss-of-function with specific differentiation stage phenotype, single lab, no molecular mechanism identified beyond the cellular phenotype\",\n      \"pmids\": [\"32457162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"AKAP8L interacts with IGF2BP1 protein and SCD1 mRNA, stabilizing SCD1 mRNA in an IGF2BP1-dependent manner in gastric cancer cells. This mechanism promotes cancer cell stemness and chemoresistance to oxaliplatin.\",\n      \"method\": \"Co-immunoprecipitation (AKAP8L–IGF2BP1), RNA immunoprecipitation (AKAP8L–SCD1 mRNA), mRNA stability assays, overexpression and knockdown in vitro and in vivo\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interactions shown, mRNA stability functionally validated, in vivo and in vitro experiments, single lab\",\n      \"pmids\": [\"36522343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In high-glucose-treated microglia, AKAP8L is upregulated and physically interacts with mTORC1 (shown by co-immunoprecipitation and proximity ligation assay). AKAP8L knockdown enhanced autophagic flux, reduced mTORC1 signaling, reduced neuroinflammation and pyroptosis, and improved cognitive function in STZ-diabetic mice, indicating AKAP8L acts upstream of mTORC1 to inhibit autophagy and promote neuroinflammation.\",\n      \"method\": \"Co-immunoprecipitation, proximity ligation assay, siRNA knockdown, rapamycin treatment, Morris water maze, autophagic flux assays, proteomics\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — interaction confirmed by two methods (co-IP + PLA), functional in vivo rescue with knockdown and pharmacological comparator, single lab\",\n      \"pmids\": [\"39033121\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SARNAclust analysis of eCLIP data identified novel RNA sequence/structure binding motifs for AKAP8L as an RNA-binding protein, indicating AKAP8L has sequence/structure-specific RNA binding activity.\",\n      \"method\": \"eCLIP data analysis, computational motif discovery (SARNAclust)\",\n      \"journal\": \"PLoS computational biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational analysis of existing eCLIP data, no direct biochemical validation of AKAP8L-specific motif\",\n      \"pmids\": [\"29596423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A PTEN–AKAP8L interaction was identified in human iPSC-derived excitatory neurons, and this interaction was shown to influence neuronal growth in the context of an ASD protein-protein interaction network.\",\n      \"method\": \"Protein-protein interaction network (AP-MS in human neurons), functional neuronal growth assay\",\n      \"journal\": \"Cell genomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — interaction identified in a network-scale study with some functional follow-up on neuronal growth; specific mechanistic details for AKAP8L are limited\",\n      \"pmids\": [\"36950384\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"AKAP8L (HAP95/NAKAP95) is a nuclear/shuttling protein that binds RNA helicase A (RHA) via its C-terminal transport domain to facilitate CTE-mediated nuclear export of unspliced retroviral mRNA; it anchors PKA regulatory subunit Iα; its N-terminal region directly binds mTORC1 in the cytoplasm to promote translation, cell growth, and proliferation; it stabilizes SCD1 mRNA through interaction with IGF2BP1; and in microglia it interacts with mTORC1 to suppress autophagy and promote neuroinflammation, while also playing a role in erythroid lineage commitment in hematopoietic stem cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"AKAP8L (HAP95/NAKAP95) is a nucleocytoplasmic shuttling protein that participates in both nuclear RNA export and cytoplasmic growth-signaling control [#0, #6]. In the nucleus it binds the C-terminal nuclear transport domain of RNA helicase A (RHA) and, through its own RHA-binding and nuclear localization domains plus a novel nuclear export signal, synergizes with RHA to drive CTE-mediated nuclear export of unspliced mRNA [#0, #1]. This RHA partnership is co-opted during HIV-1 replication, where AKAP8L associates with the reverse transcriptase region of Pol and inhibits RHA helicase activity in vitro to protect annealed tRNA-Lys3 on viral RNA [#4]. In the cytoplasm, its N-terminal region directly binds mTORC1 to promote mTORC1-mediated translation, cell growth, and proliferation, with rescue requiring the intact N-terminal mTORC1-binding region [#6]; in high-glucose-treated microglia this same interaction acts upstream of mTORC1 to suppress autophagy and promote neuroinflammation [#9]. AKAP8L additionally stabilizes SCD1 mRNA in an IGF2BP1-dependent manner to support cancer cell stemness and chemoresistance [#8], and supports erythroid lineage commitment of hematopoietic stem cells [#7]. Although it is a structural homolog of the A-kinase anchoring protein AKAP8 and can anchor the PKA regulatory subunit Iα, it lacks the canonical RII-binding motif of AKAP8 [#2, #6].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established AKAP8L as a nuclear shuttling protein that acts on retroviral RNA export by binding RNA helicase A, defining its first molecular function.\",\n      \"evidence\": \"RHA C-terminus binding, shuttling assays, and CTE reporter gene assays\",\n      \"pmids\": [\"10748171\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding region on AKAP8L not yet mapped\", \"Specificity for CTE versus Rev/RRE export explained only at the phenotypic level\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Defined AKAP8L's genomic and structural relationship to AKAP8, showing it shares NLS and zinc-finger motifs but lacks the RII-binding motif, distinguishing it from a canonical AKAP.\",\n      \"evidence\": \"cDNA cloning, chromosomal mapping, and sequence alignment\",\n      \"pmids\": [\"10697960\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Absence of RII binding inferred from sequence, not biochemically tested\", \"Functional consequence of zinc-finger motifs unknown\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Mapped the domains underlying export function, showing both RHA-binding and nuclear localization domains are required for CTE activation and that AKAP8L synergizes with RHA for unspliced mRNA export.\",\n      \"evidence\": \"Truncation/deletion mutagenesis with CTE reporter and nuclear export assays\",\n      \"pmids\": [\"11402034\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of synergy with RHA at the molecular level unresolved\", \"Endogenous cellular RNA substrates not identified\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified AKAP8L as an RNF43-interacting protein subject to proteasomal turnover, while excluding RNF43 as its ubiquitin ligase.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, MG132 treatment, and ubiquitylation assay\",\n      \"pmids\": [\"18313049\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The responsible E3 ligase remains unidentified\", \"Functional significance of the RNF43 interaction unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extended the RHA partnership to a viral mechanism, showing AKAP8L associates with HIV-1 Pol and inhibits RHA helicase activity to protect tRNA-Lys3 annealing.\",\n      \"evidence\": \"siRNA knockdown, Pol co-IP, and in vitro helicase assay with purified GST-AKAP8L\",\n      \"pmids\": [\"25034436\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; helicase inhibition shown in vitro only\", \"Whether this role applies to host RNAs not addressed\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Discovered a distinct cytoplasmic role: the N-terminal region binds mTORC1 to drive translation, growth, and proliferation, with domain-specific rescue establishing causality.\",\n      \"evidence\": \"Co-IP, pulldown, deletion/rescue, and translation/growth/proliferation assays\",\n      \"pmids\": [\"32312749\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct mTORC1 subunit contacted not pinpointed\", \"How nuclear export and mTORC1 roles are coordinated unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linked AKAP8L to a developmental process, showing it is required for erythroid lineage commitment and proliferation of hematopoietic stem cells.\",\n      \"evidence\": \"Knockdown with differentiation/apoptosis assays guided by single-cell transcriptomics\",\n      \"pmids\": [\"32457162\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular mechanism beyond the cellular phenotype\", \"Connection to its mTORC1 or RNA roles untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined an RNA-stabilizing function through IGF2BP1, showing AKAP8L stabilizes SCD1 mRNA to promote cancer stemness and chemoresistance.\",\n      \"evidence\": \"Co-IP, RNA-IP, mRNA stability assays, and in vitro/in vivo perturbation in gastric cancer cells\",\n      \"pmids\": [\"36522343\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generality of the IGF2BP1 partnership beyond SCD1 unknown\", \"Relationship to nuclear RNA export role unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected the mTORC1 interaction to a disease-relevant pathway, showing AKAP8L acts upstream of mTORC1 in microglia to suppress autophagy and drive neuroinflammation.\",\n      \"evidence\": \"Co-IP, PLA, knockdown, rapamycin comparator, and behavioral/autophagy assays in STZ-diabetic mice\",\n      \"pmids\": [\"39033121\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which AKAP8L activates mTORC1 not defined\", \"Single lab/disease model\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How AKAP8L coordinates its nuclear RNA-export functions with its cytoplasmic mTORC1-anchoring and PKA-anchoring roles, and what governs its compartment-specific partner selection, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unifying model linking RNA-binding and growth-signaling functions\", \"Structural basis of mTORC1 and RHA contacts not determined\", \"PKA-anchoring role not functionally dissected\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [0, 8]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [6, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6, 9]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"DHX9\", \"MTOR\", \"IGF2BP1\", \"RNF43\", \"PRKAR1A\", \"PTEN\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}