id: O00170 gene_symbol: AIP product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: AIP (AH receptor-interacting protein, also known as XAP2/ARA9) is a ~37 kDa, 330-amino acid FKBP-type immunophilin homolog that functions primarily as a non-enzymatic co-chaperone/scaffold in the HSP90-AHR (aryl hydrocarbon receptor) cytosolic complex. It contains an N-terminal FKBP-type PPIase-like domain that is catalytically inactive (lacking PPIase enzymatic activity and FK506/rapamycin binding) and C-terminal TPR repeats (three TPR motifs plus a terminal alpha-7 helix) that mediate interactions with HSP90 and TOMM20. Cryo-EM structural analysis of the human agonist-bound AHR cytosolic complex (DOI:10.1038/s41467-022-34773-w) reveals AIP/XAP2 acting as a structural brace associated with the HSP90 dimer and the AHR client, with the HSP90 C-terminal MEEVD motif docked into the TPR domain of AIP. AIP has also been reported to facilitate TOMM20-dependent mitochondrial preprotein import and to suppress thermal aggregation of model substrates in vitro, consistent with a holdase-like assay result in this import context rather than a broad protein-folding chaperone role. Beyond the AHR complex, AIP also interacts with phosphodiesterases PDE4A5 and PDE2A3, linking it to localized cAMP regulation and modulation of AHR nuclear translocation. Proteomic studies show AIP co-localizes with HSPA9 in the mitochondrial chaperone network, consistent with mitochondrial chaperone-network association (DOI:10.18632/oncotarget.24183). Germline loss-of-function AIP variants predispose to pituitary neuroendocrine tumors (PitNETs) with incomplete penetrance (~12-30%), behaving as a tumor suppressor with a two-hit model (loss of heterozygosity in tumors). AIP mutations account for ~29% of childhood-onset GH-secreting pituitary tumors presenting as gigantism and ~9% of macroprolactinomas presenting before age 20 (DOI:10.1038/s41574-023-00948-8). existing_annotations: - term: id: GO:0045893 label: positive regulation of DNA-templated transcription evidence_type: IEA original_reference_id: GO_REF:0000108 review: summary: This IEA annotation was inferred by logical inference from AIP having transcription coactivator activity (GO:0003713). AIP/XAP2 was shown by Meyer et al. (PMID:9447995) to enhance AhR-driven transcription from a dioxin-responsive element by about twofold. This is an indirect consequence of AIP stabilizing the AHR-HSP90 complex in the cytosol, not a direct transcriptional activation function. The annotation is logically consistent with the coactivator annotation but represents a secondary downstream effect rather than a core function of AIP. action: KEEP_AS_NON_CORE reason: AIP does enhance AhR-driven transcription, but this is an indirect effect of its co-chaperone function in stabilizing the AHR-HSP90 complex, not a direct transcriptional regulatory activity. The annotation is technically correct as an inference from the coactivator annotation, but represents a downstream biological consequence rather than core function. supported_by: - reference_id: PMID:9447995 supporting_text: XAP2 enhanced the ability of endogenous murine and human AhR complexes to activate a dioxin-responsive element-luciferase reporter twofold, following transient expression of XAP2 in Hepa 1c1c7 and HeLa cells. - term: id: GO:0003755 label: peptidyl-prolyl cis-trans isomerase activity evidence_type: IEA original_reference_id: GO_REF:0000002 review: summary: This IEA annotation was automatically assigned based on InterPro domain IPR001179 (FKBP-type PPIase domain). While AIP does contain an FKBP-type PPIase-like domain, multiple studies have shown this domain is catalytically inactive. Laenger et al. (PMID:19375531) explicitly demonstrated that the PPIase-like region of XAP2 is enzymatically inactive. The domain has diverged from catalytically active FKBP family members and lacks key residues for PPIase catalysis. The Proteostasis PN projection classifies AIP under an FKBP-type PPIase branch, but that family-level projection is not accepted at gene level because direct evidence shows AIP lacks PPIase activity. action: REMOVE reason: AIP contains an FKBP-type PPIase-like domain that is catalytically inactive (PMID:19375531). The InterPro domain match is structurally correct but the functional annotation of PPIase activity is incorrect for this protein. This is a well-documented case of a domain homolog that has lost enzymatic activity. Therefore the PN peptidyl-prolyl isomerase projection should not be propagated for AIP. additional_reference_ids: - file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv supported_by: - reference_id: PMID:19375531 supporting_text: The PPIase-like region turned out to be enzymatically inactive. Thus, PPIase activity is not essential for the action of XAP2 on GR, similarly to FKBP51 and FKBP52. - reference_id: file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv supporting_text: The PN projection records AIP to GO:0003755 peptidyl-prolyl cis-trans isomerase activity with goa_status already_in_goa_exact. - term: id: GO:0005737 label: cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000044 review: summary: This IEA annotation is based on UniProtKB/Swiss-Prot Subcellular Location mapping. AIP is well-established as a cytoplasmic protein. Kuzhandaivelu et al. (PMID:8972861) showed by immunofluorescence that XAP2 is a cytoplasmic protein. UniProt CC line states Subcellular location as Cytoplasm. This is consistent with AIP functioning as a cytosolic co-chaperone in the AHR-HSP90 complex and as a cytosolic factor in mitochondrial preprotein import. action: ACCEPT reason: AIP is well-established as a cytoplasmic protein across multiple studies. This is consistent with its function as a cytosolic co-chaperone. supported_by: - reference_id: PMID:8972861 supporting_text: Antiserum raised against XAP2 recognizes a cytoplasmic protein with an apparent molecular mass of 36 kDa. - term: id: GO:0051082 label: unfolded protein binding evidence_type: IEA original_reference_id: GO_REF:0000117 review: summary: This IEA annotation of GO:0051082 (unfolded protein binding) was assigned by ARBA machine learning models. GO:0051082 is being obsoleted (go-ontology issue 30962). The UNFOLDED_PROTEIN_BINDING project classifies AIP as a gene-specific replacement case rather than a foldase/holdase case. AIP's best-established molecular function is TPR-mediated HSP90 binding in the AHR-HSP90 co-chaperone complex. Although PMID:14557246 reported chaperone-like aggregation suppression in mitochondrial preprotein import assays, this is not strong enough to make GO:0044183 (protein folding chaperone) the preferred replacement for AIP. action: MODIFY reason: GO:0051082 is being obsoleted, and the project-level decision for AIP is to reclassify this annotation to GO:0051879 (Hsp90 protein binding). This captures AIP's specific, well-supported co-chaperone/scaffold activity without overgeneralizing AIP as a protein folding chaperone. proposed_replacement_terms: - id: GO:0051879 label: Hsp90 protein binding additional_reference_ids: - PMID:19375531 - PMID:28634279 supported_by: - reference_id: PMID:19375531 supporting_text: The effect of XAP2 on GR requires its interaction with Hsp90 through the TPR motif. - reference_id: PMID:28634279 supporting_text: The results of a co-immunoprecipitation experiment with mutant AIP and HSP90 were consistent with lack of interaction between the two proteins. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:17329248 review: summary: This IPI annotation records the interaction between AIP (XAP2) and PDE2A (UniProtKB:O00408). De Oliveira et al. (PMID:17329248) identified XAP2 as a major PDE2A-interacting protein via yeast two-hybrid screening and mapped the binding site to the GAF-B domain of PDE2A. This is a functionally significant interaction as PDE2A binding to XAP2 inhibits TCDD- and cAMP-induced nuclear translocation of AhR in hepatocytes. The interaction is relevant to AIP function in cAMP signaling regulation. However, protein binding is uninformative; the more specific annotation GO:0036004 (GAF domain binding) already captures this interaction. action: ACCEPT reason: The interaction between AIP and PDE2A is well-documented by yeast two-hybrid and co-immunoprecipitation (PMID:17329248). While protein binding is a generic term, the IPI evidence with specific interactor is standard practice and the more specific GAF domain binding annotation is also present. Duplicates with different evidence lines are acceptable. supported_by: - reference_id: PMID:17329248 supporting_text: In a yeast two-hybrid screening we identified XAP2, a crucial component of the aryl hydrocarbon receptor (AhR) complex, as a major PDE2A-interacting protein. We mapped the XAP2 binding site to the GAF-B domain of PDE2A. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:19375531 review: summary: This IPI annotation records the interaction between AIP (XAP2) and HSP90AB1 (UniProtKB:P08238). Laenger et al. (PMID:19375531) showed that XAP2 interacts with Hsp90 through its TPR motif and that this interaction is required for XAP2 to inhibit glucocorticoid receptor activity. The AIP-HSP90 interaction is one of the most well-characterized interactions for this protein, mediated by the TPR domain binding to the MEEVD motif at the C-terminus of HSP90. This is a core interaction of AIP. action: ACCEPT reason: The AIP-HSP90 interaction is a core functional interaction, extensively validated. This IPI evidence from PMID:19375531 provides additional confirmation that the TPR domain mediates the HSP90 binding. Multiple independent studies confirm this interaction. supported_by: - reference_id: PMID:19375531 supporting_text: The effect of XAP2 on GR requires its interaction with Hsp90 through the TPR motif. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:20029029 review: summary: This IPI annotation records the interaction between AIP and EGFR (UniProtKB:P00533) from a study on HDAC6 regulation of EGFR trafficking (PMID:20029029). AIP was not the focus of this study. The interaction between AIP and EGFR is likely detected in a high-throughput context and may represent an indirect interaction mediated through the HSP90 chaperone machinery, since EGFR is a known HSP90 client. Without more specific evidence for a direct, functional AIP-EGFR interaction, this should be considered with caution. action: UNDECIDED reason: >- The cached publication describes an EGFR interactome screen but does not provide enough accessible detail here to verify the specific AIP-EGFR pair or its directness. This should not be treated as a core AIP function; retain for expert review of the underlying IntAct evidence. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:21170051 review: summary: This IPI annotation records the interaction between AIP and HSP90AB1 (UniProtKB:P08238) from a study on mixed Hsp90-cochaperone complexes (PMID:21170051). This study demonstrates that AIP forms part of mixed HSP90 co-chaperone complexes important for the chaperone reaction cycle. This is consistent with AIP being a bona fide HSP90 co-chaperone via its TPR domain. action: ACCEPT reason: This confirms the well-established AIP-HSP90 co-chaperone interaction in the context of functional chaperone cycle complexes. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:21903422 review: summary: This IPI annotation records the interaction between AIP and IRF7 (UniProtKB:Q92985) from a study mapping innate immunity protein interaction networks (PMID:21903422). AIP was detected interacting with IRF7 in a high-throughput innate immunity interaction mapping study. AIP is not known to have a role in interferon signaling. This interaction may be indirect (mediated through HSP90 which is known to interact with various signaling proteins) or may represent a non-physiological interaction from the high-throughput screen. action: UNDECIDED reason: >- The cached paper describes a systematic innate-immunity interactome, but the accessible text does not verify the specific AIP-IRF7 interaction or establish relevance to AIP function. This generic protein-binding call should not be accepted as core AIP biology. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:22113938 review: summary: This IPI annotation records the interaction between AIP and CSNK2A1/CK2alpha (UniProtKB:P68400) from a large-scale kinase substrate identification study (PMID:22113938). The interaction is from a high-throughput bead-based screen. CK2 is a ubiquitous kinase and the interaction may or may not be physiologically significant for AIP function. AIP has a phosphoserine at position 43 (ECO:0007744|PubMed:23186163), which could be a CK2 substrate site. action: UNDECIDED reason: >- The interaction comes from a large-scale kinase substrate screen, but the cached text does not provide enough specific support for an AIP-CK2alpha interaction or its functional relevance. This should remain a non-core item for expert review, not an accepted core annotation. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25036637 review: summary: This IPI annotation records the interaction between AIP and HSP90AB1 (UniProtKB:P08238) from a quantitative chaperone interaction network study (PMID:25036637). This study systematically mapped the chaperone-cochaperone interaction network and places AIP firmly within the HSP90 co-chaperone system. This is one of the core interactions of AIP. action: ACCEPT reason: This further validates the well-established AIP-HSP90 co-chaperone interaction in a comprehensive chaperone interactome study. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:28514442 review: summary: This IPI annotation records the interaction between AIP and PRAMEF10 (UniProtKB:O60809) from a large-scale interactome mapping study (PMID:28514442). PRAMEF10 is a PRAME family member. This is from a high-throughput study and the biological significance of AIP interacting with PRAMEF10 is unclear. PRAMEF10 is poorly characterized. action: UNDECIDED reason: >- This derives from a proteome-scale interactome study, and the cached text does not verify the specific AIP-PRAMEF10 interaction. PRAMEF10 is not part of the established AIP-HSP90/AHR tumor-suppressor mechanism, so the generic binding annotation should not be accepted as core. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:28634279 review: summary: This IPI annotation records the interaction between AIP and HSP90AB1 (UniProtKB:P08238) from Salvatori et al. (PMID:28634279), which studied the c.805_825dup AIP mutation. The study demonstrated by co-immunoprecipitation that wild-type AIP interacts with HSP90, and that the p.F269_H275dup mutation in TPR3 disrupts this interaction. This provides important functional validation that the AIP-HSP90 interaction is mediated through the TPR domain and is disrupted by disease-causing mutations. action: ACCEPT reason: This co-immunoprecipitation study confirms the AIP-HSP90 interaction and demonstrates its functional importance, as disease-causing AIP mutations disrupt the HSP90 binding. This is directly relevant to the tumor suppressor function of AIP. supported_by: - reference_id: PMID:28634279 supporting_text: The results of a co-immunoprecipitation experiment with mutant AIP and HSP90 were consistent with lack of interaction between the two proteins (Fig - reference_id: PMID:28634279 supporting_text: The mutation results in the duplication of seven amino-acids in third TPR domain of AIP, leading to the disruption of protein-protein interactions and markedly reduced protein stability. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:31980649 review: summary: This IPI annotation records the interaction between AIP and EGFR (UniProtKB:P00533) from a study on EGFR network rewiring in KRAS-mutant colorectal cancer cells (PMID:31980649). AIP was not the focus of this study. The interaction with EGFR is likely indirect, mediated through the HSP90 chaperone machinery. action: UNDECIDED reason: >- The cached publication describes EGFR network remodeling, but it does not provide enough accessible detail to verify the specific AIP-EGFR pair or distinguish direct binding from indirect HSP90-system association. This is not a core AIP function. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:33961781 review: summary: This IPI annotation records interactions between AIP and PRAMEF10 (UniProtKB:O60809) and/or SYCN (UniProtKB:Q0VAF6) from a dual proteome-scale network study (PMID:33961781). These are from a high-throughput interactome study. The biological significance of these interactions for AIP function is unclear. action: UNDECIDED reason: >- The interaction comes from a systematic proteome-scale network study, but the cached text does not verify the specific AIP-PRAMEF10/SYCN pair(s). Their relevance to AIP function is unclear, so this generic binding annotation should not be accepted as core. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:35271311 review: summary: This IPI annotation records the interaction between AIP and CSNK2A1/CK2alpha (UniProtKB:P68400) from the OpenCell study (PMID:35271311), a large-scale endogenous tagging and imaging study. This is a second independent confirmation of the AIP-CK2alpha interaction after PMID:22113938. action: UNDECIDED reason: >- The OpenCell paper is a large-scale localization and interaction resource, but the cached text does not provide specific support for the AIP-CK2alpha pair. Treat this as an unresolved, non-core protein-binding record rather than accepted AIP biology. - term: id: GO:0003712 label: transcription coregulator activity evidence_type: IEA original_reference_id: GO_REF:0000107 review: summary: This IEA annotation was transferred from the mouse ortholog via Ensembl Compara. AIP/XAP2 was shown to enhance AhR-mediated transcription (PMID:9447995), which is the basis for the mouse ortholog annotation. The term GO:0003712 (transcription coregulator activity) is broader than the TAS annotation GO:0003713 (transcription coactivator activity) also present for this gene. AIP enhances AhR transcription indirectly by stabilizing the cytosolic AHR-HSP90 complex, not by acting as a direct transcriptional coregulator in the nucleus. This is a secondary consequence of its co-chaperone function. action: KEEP_AS_NON_CORE reason: AIP does enhance AhR-dependent transcription, but this is an indirect effect of its co-chaperone role in stabilizing the AHR complex. The broader IEA term is acceptable as a non-core annotation consistent with the TAS coactivator annotation. supported_by: - reference_id: PMID:9447995 supporting_text: XAP2 enhanced the ability of endogenous murine and human AhR complexes to activate a dioxin-responsive element-luciferase reporter twofold, following transient expression of XAP2 in Hepa 1c1c7 and HeLa cells. - term: id: GO:0005829 label: cytosol evidence_type: IEA original_reference_id: GO_REF:0000107 review: summary: This IEA annotation was transferred from the mouse ortholog via Ensembl Compara. AIP is established as a cytosolic protein by multiple lines of evidence including IDA annotations based on immunofluorescence (GO_REF:0000052) and direct experimental evidence (PMID:17329248). This IEA is consistent with and redundant with the experimental evidence. action: ACCEPT reason: Cytosolic localization of AIP is well-established by multiple experimental methods. This IEA is consistent with experimental evidence. - term: id: GO:0016020 label: membrane evidence_type: IEA original_reference_id: GO_REF:0000107 review: summary: This IEA annotation was transferred from the mouse ortholog via Ensembl Compara. AIP is primarily a cytosolic protein. The membrane annotation may reflect AIP association with the outer mitochondrial membrane via its interaction with TOMM20 (PMID:14557246), or its reported colocalization with the plasma membrane via PDE2A interaction (PMID:17329248). AIP itself is not a membrane protein and does not have a transmembrane domain. The term GO:0016020 (membrane) is very broad and not very informative. action: MARK_AS_OVER_ANNOTATED reason: AIP is not an integral membrane protein. While it may associate with membranes through protein-protein interactions (TOMM20 at the mitochondrial outer membrane, or PDE2A at the plasma membrane), the broad term "membrane" is uninformative and potentially misleading for a primarily cytosolic co-chaperone protein. More specific localization terms (cytosol, plasma membrane colocalization) are already captured by other annotations. - term: id: GO:0017162 label: aryl hydrocarbon receptor binding evidence_type: IEA original_reference_id: GO_REF:0000107 review: summary: This IEA annotation was transferred from the mouse ortholog via Ensembl Compara. AIP/XAP2 was originally identified as a component of the AhR core complex (PMID:9447995). Meyer et al. showed that XAP2 coprecipitates with FLAG-tagged AhR and is present in the unliganded AhR 9S complex. AIP binding to AhR is well-established as a core function of this protein and is the basis for its name. action: ACCEPT reason: AIP binding to the aryl hydrocarbon receptor is one of its best-characterized functions. This was demonstrated by coprecipitation and is the basis for the protein name. The IEA transfer from mouse ortholog is appropriate. supported_by: - reference_id: PMID:9447995 supporting_text: Here we report the purification of an approximately 38-kDa protein (p38) from COS-1 cell cytosol that is a member of this complex by coprecipitation with a FLAG-tagged AhR. - reference_id: file:human/AIP/AIP-deep-research-falcon.md supporting_text: >- AIP participates in a cytosolic multiprotein complex with AHR and HSP90 (and p23), regulating AHR stability/cytosolic retention and nuclear translocation following ligand activation. - term: id: GO:0034751 label: aryl hydrocarbon receptor complex evidence_type: IEA original_reference_id: GO_REF:0000107 review: summary: This IEA annotation was transferred from the mouse ortholog via Ensembl Compara. AIP/XAP2 is an established subunit of the unliganded AhR core complex (PMID:9447995). Meyer et al. demonstrated that XAP2 is part of the heterotetrameric 9S AhR complex consisting of AhR, two HSP90 molecules, and XAP2. Reactome entries (R-HSA-8936849, R-HSA-8937169) also model AIP as part of the AHR:2xHSP90:AIP:PTGES3 complex. This is a core localization for AIP. action: ACCEPT reason: AIP is a bona fide subunit of the aryl hydrocarbon receptor complex. This is one of the defining characteristics of this protein and is supported by multiple independent studies and Reactome pathway models. supported_by: - reference_id: PMID:9447995 supporting_text: Prior to ligand activation, the unactivated aryl hydrocarbon receptor (AhR) exists in a heterotetrameric 9S core complex consisting of the AhR ligand-binding subunit, a dimer of hsp90, and an unknown subunit. - term: id: GO:0005829 label: cytosol evidence_type: IDA original_reference_id: GO_REF:0000052 review: summary: This IDA annotation is based on curation of immunofluorescence data (HPA). Cytosolic localization of AIP is well-established and consistent with its function as a cytosolic co-chaperone. Multiple studies confirm AIP is primarily cytosolic (PMID:8972861, PMID:14557246, PMID:17329248). action: ACCEPT reason: Immunofluorescence-based evidence for cytosolic localization of AIP is consistent with extensive other evidence for cytosolic localization. - term: id: GO:0003755 label: peptidyl-prolyl cis-trans isomerase activity evidence_type: IDA original_reference_id: PMID:14557246 review: summary: This IDA annotation citing PMID:14557246 (Yano et al. 2003) claims PPIase activity for AIP. However, Yano et al. 2003 does NOT demonstrate PPIase enzymatic activity for AIP. The paper focuses on AIP as a mitochondrial import mediator with chaperone-like holdase activity. AIP belongs to the FKBP PPIase family structurally but its PPIase domain is catalytically inactive. Laenger et al. (PMID:19375531) explicitly showed the PPIase-like region is enzymatically inactive. This IDA annotation appears to be an error in the original curation, conflating structural homology to PPIases with actual catalytic activity. The Proteostasis PN projection repeats this structural-family inference through the FKBP-type PPIase branch, but the gene-level biochemical evidence argues against accepting the projection for AIP. action: REMOVE reason: AIP does not have PPIase catalytic activity. PMID:14557246 does not demonstrate PPIase activity; it describes chaperone-like holdase activity and mitochondrial import function. PMID:19375531 explicitly demonstrated that the PPIase-like region of AIP is enzymatically inactive. The IDA annotation based on PMID:14557246 for PPIase activity is an error. The PN FKBP/PPIase classification should therefore be treated as over-broad for AIP rather than as support for retaining GO:0003755. additional_reference_ids: - file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv supported_by: - reference_id: PMID:19375531 supporting_text: The PPIase-like region turned out to be enzymatically inactive. - reference_id: PMID:14557246 supporting_text: AIP belongs to a family of peptidyl-prolyl cis/trans isomerases (PPIases) that are ubiquitous in prokaryotes and eukaryotes (Galat and Metcalfe, 1995). - reference_id: file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv supporting_text: The PN projection records AIP to GO:0003755 peptidyl-prolyl cis-trans isomerase activity with goa_status already_in_goa_exact. - term: id: GO:0051604 label: protein maturation evidence_type: IDA original_reference_id: PMID:14557246 review: summary: This IDA annotation to GO:0051604 (protein maturation) cites Yano et al. (PMID:14557246). The paper demonstrates that AIP functions as a cytosolic factor mediating mitochondrial preprotein import. AIP maintains preproteins in an import-competent conformation and facilitates their import into mitochondria via interaction with TOMM20. Overexpression of AIP enhanced mature OTC production (processing of pOTC to mature OTC by mitochondrial import and cleavage), and depletion reduced it. While the end result is maturation of mitochondrial preproteins (signal peptide cleavage), AIP does not directly participate in the proteolytic processing. A more accurate annotation would be GO:0070585 (protein localization to mitochondrion), which is already annotated. action: MARK_AS_OVER_ANNOTATED reason: AIP facilitates mitochondrial import but does not directly participate in protein maturation (proteolytic processing). The observed effect on pOTC maturation is an indirect consequence of enhanced mitochondrial import. The more appropriate annotation GO:0070585 (protein localization to mitochondrion) is already present for this gene and this reference. GO:0051604 is too broad and somewhat misleading for what AIP actually does. supported_by: - reference_id: PMID:14557246 supporting_text: AIP can enhance the mitochondrial import of pOTC. - reference_id: PMID:14557246 supporting_text: All these results suggest strongly that AIP stabilizes pOTC in the cytosol and facilitates its import into mitochondria. - term: id: GO:0005654 label: nucleoplasm evidence_type: TAS original_reference_id: Reactome:R-HSA-8937169 review: summary: This TAS annotation is based on Reactome pathway R-HSA-8937169 (AHR:TCDD:2xHSP90AB1:AIP:PTGES3 translocates from cytosol to nucleoplasm). In the Reactome model, the entire AHR complex including AIP translocates to the nucleus upon ligand binding. AIP is primarily cytosolic and its presence in the nucleoplasm is transient as part of the ligand-bound AHR complex before the complex dissociates. This is a non-core localization. action: KEEP_AS_NON_CORE reason: AIP transiently enters the nucleoplasm as part of the ligand-activated AHR-HSP90 complex, but this is not its primary localization. The Reactome pathway model is accurate for the transient translocation event. - term: id: GO:0005654 label: nucleoplasm evidence_type: TAS original_reference_id: Reactome:R-HSA-8937191 review: summary: This TAS annotation is based on Reactome pathway R-HSA-8937191 (AHR:TCDD:2xHSP90AB1:AIP:PTGES3 dissociates). This represents the dissociation of the AHR complex in the nucleoplasm after translocation. AIP is released from the complex in the nucleus. This is consistent with the transient nuclear localization of AIP during AHR signaling. action: KEEP_AS_NON_CORE reason: This represents transient nuclear localization of AIP during AHR signaling, consistent with the Reactome pathway model. Not the primary localization. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8936849 review: summary: This TAS annotation is based on Reactome pathway R-HSA-8936849 (AHR:2xHSP90:AIP:PTGES3 binds TCDD). AIP is part of the cytosolic AHR complex that binds the TCDD ligand. Cytosolic localization of AIP is well-established. action: ACCEPT reason: Cytosolic localization of AIP as part of the AHR complex is well-supported by multiple lines of evidence. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8937169 review: summary: This TAS annotation is based on Reactome pathway R-HSA-8937169 (AHR:TCDD:2xHSP90AB1:AIP:PTGES3 translocates from cytosol to nucleoplasm). AIP starts in the cytosol as part of the AHR complex. Cytosol is the primary localization. action: ACCEPT reason: Cytosolic localization is the primary and well-established localization for AIP. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-8950201 review: summary: This TAS annotation is based on Reactome pathway R-HSA-8950201 (Expression of Aryl Hydrocarbon receptor-interacting protein). AIP is expressed and localized in the cytosol. This is consistent with all other evidence. action: ACCEPT reason: Cytosolic localization of AIP is the primary and well-established localization, supported by all available evidence. - term: id: GO:0036004 label: GAF domain binding evidence_type: IDA original_reference_id: PMID:17329248 review: summary: This IDA annotation to GO:0036004 (GAF domain binding) is based on de Oliveira et al. (PMID:17329248), which showed that XAP2 binds to the GAF-B domain of PDE2A. The binding was identified by yeast two-hybrid and confirmed by immunoprecipitation. The GAF-B domain was specifically mapped as the XAP2 binding site. This is a well-characterized, specific molecular interaction. action: ACCEPT reason: The interaction between AIP/XAP2 and the GAF-B domain of PDE2A was specifically mapped and validated by multiple methods (yeast two-hybrid and co-immunoprecipitation). This is a specific and informative MF annotation. supported_by: - reference_id: PMID:17329248 supporting_text: We mapped the XAP2 binding site to the GAF-B domain of PDE2A. - term: id: GO:0005829 label: cytosol evidence_type: IDA original_reference_id: PMID:17329248 review: summary: This IDA annotation for cytosol localization is based on de Oliveira et al. (PMID:17329248), which performed immunofluorescence showing XAP2 in the cytosol. The study also showed that PDE2A colocalizes with XAP2 in the cytosol and at the plasma membrane. action: ACCEPT reason: Cytosolic localization demonstrated by immunofluorescence is consistent with all other evidence for AIP being primarily a cytosolic protein. - term: id: GO:0005886 label: plasma membrane evidence_type: IDA original_reference_id: PMID:17329248 review: summary: This IDA annotation with qualifier colocalizes_with records that AIP/XAP2 colocalizes with the plasma membrane, based on de Oliveira et al. (PMID:17329248). The study showed XAP2 and PDE2A colocalize at the plasma membrane in addition to the cytosol. This likely reflects AIP being recruited to the plasma membrane through its interaction with PDE2A, which has membrane association. This is a secondary, non-core localization dependent on the PDE2A interaction. action: KEEP_AS_NON_CORE reason: Plasma membrane colocalization is a secondary localization dependent on the interaction with PDE2A. AIP is primarily a cytosolic protein and does not have intrinsic membrane targeting. The colocalizes_with qualifier appropriately indicates indirect association. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:14557246 review: summary: This IPI annotation records AIP interactions with Hsc70 (UniProtKB:P11142), TOMM20 (UniProtKB:Q15388), and/or TOMM20L (UniProtKB:Q9NS69) from Yano et al. (PMID:14557246). The paper demonstrated by two-hybrid and in vitro binding that AIP interacts with TOMM20 via its TPR domain and with Hsc70. AIP forms a ternary complex with preproteins and TOMM20. These are core, functionally important interactions for AIP's role in mitochondrial preprotein import. action: ACCEPT reason: The interactions of AIP with TOMM20 and Hsc70 demonstrated in PMID:14557246 are core to its mitochondrial import mediator function. The binding was validated by multiple methods including two-hybrid, in vitro binding, and co-precipitation. supported_by: - reference_id: PMID:14557246 supporting_text: Using two-hybrid screening, we identified arylhydrocarbon receptor-interacting protein (AIP), an FK506-binding protein homologue, interacting with Tom20. - reference_id: PMID:14557246 supporting_text: Hsc70 was also found to bind to AIP. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: PMID:14557246 review: summary: This TAS annotation for cytosol localization cites Yano et al. (PMID:14557246). The paper demonstrates AIP functions as a cytosolic factor mediating preprotein import into mitochondria. AIP was detected in cytosolic fractions of HeLa, HepG2, COS-7, and Hepa1c1c7 cells by immunoblot. action: ACCEPT reason: Cytosolic localization of AIP is well-documented by immunoblot analysis in multiple cell lines in this paper and is consistent with all other evidence. supported_by: - reference_id: PMID:14557246 supporting_text: When immunoblot analysis was done using anti-human AIP, AIP polypeptides were readily detected in the lysates of HeLa (human), HepG2 (human), COS-7 (monkey), and Hepa1c1c7 (mouse) cells. - term: id: GO:0051082 label: unfolded protein binding evidence_type: IDA original_reference_id: PMID:14557246 review: summary: This IDA annotation to GO:0051082 (unfolded protein binding) is based on Yano et al. 2003 (PMID:14557246), which showed that AIP binds mitochondrial preproteins, interacts with TOMM20, maintains preornithine transcarbamylase import competency, and suppresses thermal aggregation of rhodanese and citrate synthase in vitro. Those data support AIP's role in mitochondrial preprotein import and show a holdase-like assay result, but the UNFOLDED_PROTEIN_BINDING project treats AIP as a gene-specific replacement case rather than a general foldase/holdase case. AIP's best-established molecular function remains TPR-mediated HSP90 binding in the AHR-HSP90 co-chaperone complex. action: MODIFY reason: GO:0051082 is being obsoleted. The PMID:14557246 data do not justify promoting AIP to the broad GO:0044183 protein folding chaperone term under this project's decision rules; they are better captured by AIP's accepted mitochondrial preprotein import and TOMM20/preprotein interaction annotations. For the GO:0051082 replacement, use GO:0051879 (Hsp90 protein binding), which captures the specific, well-supported co-chaperone/scaffold molecular function of AIP. proposed_replacement_terms: - id: GO:0051879 label: Hsp90 protein binding additional_reference_ids: - PMID:19375531 - PMID:28634279 supported_by: - reference_id: PMID:14557246 supporting_text: These results suggest that AIP functions as a cytosolic factor that mediates preprotein import into mitochondria. - reference_id: PMID:14557246 supporting_text: An aggregation suppression assay indicated that AIP has a chaperone-like activity to prevent substrate proteins from aggregation. - reference_id: PMID:19375531 supporting_text: The effect of XAP2 on GR requires its interaction with Hsp90 through the TPR motif. - term: id: GO:0070585 label: protein localization to mitochondrion evidence_type: IDA original_reference_id: PMID:14557246 review: summary: This IDA annotation to GO:0070585 (protein localization to mitochondrion) is based on Yano et al. (PMID:14557246), which provides extensive evidence that AIP mediates mitochondrial preprotein import. Key evidence includes in vitro import assays showing AIP maintains pOTC import competency, cell-based assays showing AIP overexpression enhances pOTC import by ~3-fold, siRNA depletion of AIP impairing pOTC import to ~40% of control, AIP binding specifically to mitochondrial preproteins via their presequences, AIP forming ternary complexes with preproteins and TOMM20, and AIP having chaperone-like activity to prevent preprotein aggregation. This is a well-supported core function of AIP. action: ACCEPT reason: The evidence for AIP mediating protein localization to mitochondria is extensive and robust, including in vitro import assays, overexpression and depletion experiments in cells, specific binding to preproteins and TOMM20, and ternary complex formation. This represents a core function of AIP alongside its role in the AHR-HSP90 complex. supported_by: - reference_id: PMID:14557246 supporting_text: These results suggest that AIP functions as a cytosolic factor that mediates preprotein import into mitochondria. - reference_id: PMID:14557246 supporting_text: Thus, depletion of AIP reduced the mitochondrial import of pOTC, which means that endogenous AIP facilitates pOTC import into mitochondria. - reference_id: PMID:14557246 supporting_text: Formation of a ternary complex of Tom20, AIP, and preprotein was observed. - term: id: GO:0003713 label: transcription coactivator activity evidence_type: TAS original_reference_id: PMID:9447995 review: summary: This TAS annotation to GO:0003713 (transcription coactivator activity) is based on Meyer et al. (PMID:9447995), which showed that XAP2 enhanced AhR-driven transcription of a dioxin-responsive element reporter by about twofold when transiently expressed in Hepa 1c1c7 and HeLa cells. However, AIP does not function as a classical transcription coactivator. AIP enhances AhR signaling indirectly by stabilizing the cytosolic AHR-HSP90 complex, improving AhR receptivity for ligand and/or nuclear targeting. AIP does not directly contact DNA or recruit transcriptional machinery. The term "transcription coactivator activity" implies direct participation in transcriptional activation, which overstates AIP's role. A more accurate description would be that AIP modulates AhR signaling through its co-chaperone function. action: MARK_AS_OVER_ANNOTATED reason: AIP enhances AhR-driven transcription indirectly through its co-chaperone function in the AHR-HSP90 complex, not by acting as a direct transcription coactivator. The twofold enhancement of reporter activity (PMID:9447995) reflects improved AhR complex stability and signaling, not direct transcriptional coactivation. Calling AIP a transcription coactivator overstates its molecular role and is misleading about its mechanism of action. supported_by: - reference_id: PMID:9447995 supporting_text: XAP2 enhanced the ability of endogenous murine and human AhR complexes to activate a dioxin-responsive element-luciferase reporter twofold, following transient expression of XAP2 in Hepa 1c1c7 and HeLa cells. - reference_id: PMID:9447995 supporting_text: It was not required for the assembly of an AhR-hsp90 complex in vitro. Additionally, XAP2 did not directly associate with hsp90 upon in vitro translation, but was present in a 9S form when cotranslated in vitro with murine AhR. - term: id: GO:0005737 label: cytoplasm evidence_type: TAS original_reference_id: PMID:8972861 review: summary: This TAS annotation for cytoplasm is based on Kuzhandaivelu et al. (PMID:8972861), the original paper identifying XAP2 as a hepatitis B virus X-associated protein. The paper showed by immunostaining with anti-XAP2 antiserum that XAP2 is a cytoplasmic protein with apparent molecular mass of 36 kDa. action: ACCEPT reason: Cytoplasmic localization of AIP/XAP2 was directly demonstrated by immunostaining in the original characterization paper and is consistent with all subsequent evidence. supported_by: - reference_id: PMID:8972861 supporting_text: Antiserum raised against XAP2 recognizes a cytoplasmic protein with an apparent molecular mass of 36 kDa. core_functions: - molecular_function: id: GO:0051879 label: Hsp90 protein binding description: >- AIP/XAP2 binds HSP90 via its C-terminal TPR domain (three TPR motifs plus a terminal alpha-7 helix), serving as a co-chaperone/scaffold in the AHR-HSP90 complex. The TPR domain engages the MEEVD motif at the HSP90 C-terminus (PDB:4APO). Cryo-EM structure of the human agonist-bound HSP90-XAP2-AHR cytosolic complex (DOI:10.1038/s41467-022-34773-w) reveals AIP acting as a structural brace associated with the HSP90 dimer and the AHR client, with the MEEVD motif docked into the TPR domain of AIP, consistent with canonical TPR-mediated recruitment of HSP90 co-chaperones. Disease-causing mutations in the TPR domain disrupt HSP90 binding and are associated with pituitary neuroendocrine tumor predisposition (PitNET/PITA1), consistent with a two-hit tumor suppressor model (loss of heterozygosity in tumors). locations: - id: GO:0005829 label: cytosol in_complex: id: GO:0034751 label: aryl hydrocarbon receptor complex supported_by: - reference_id: PMID:19375531 supporting_text: >- The effect of XAP2 on GR requires its interaction with Hsp90 through the TPR motif. - reference_id: PMID:28634279 supporting_text: >- The mutation results in the duplication of seven amino-acids in third TPR domain of AIP, leading to the disruption of protein-protein interactions and markedly reduced protein stability. - molecular_function: id: GO:0017162 label: aryl hydrocarbon receptor binding description: >- AIP/XAP2 is a stoichiometric component of the unliganded AHR 9S core complex (AHR:2xHSP90:AIP:PTGES3), binding directly to the aryl hydrocarbon receptor. It stabilizes the cytosolic AHR-HSP90 complex, enhancing AhR receptivity for ligand and subsequent transcriptional activation. Cryo-EM structural analysis (DOI:10.1038/s41467-022-34773-w) confirms the architectural arrangement of AIP as a brace spanning the HSP90 dimer and AHR client within this complex. locations: - id: GO:0005829 label: cytosol in_complex: id: GO:0034751 label: aryl hydrocarbon receptor complex supported_by: - reference_id: PMID:9447995 supporting_text: >- Here we report the purification of an approximately 38-kDa protein (p38) from COS-1 cell cytosol that is a member of this complex by coprecipitation with a FLAG-tagged AhR. - molecular_function: id: GO:0036004 label: GAF domain binding description: >- AIP binds to the GAF-B domain of phosphodiesterase 2A (PDE2A), an interaction that inhibits TCDD- and cAMP-induced nuclear translocation of AhR in hepatocytes, providing a regulatory link between cAMP signaling and the AhR pathway. AIP also interacts with PDE4A5, further linking it to localized cAMP regulation (DOI:10.1586/eem.10.42). These phosphodiesterase interactions suggest AIP may modulate pituitary tumor biology through cAMP pathway effects. locations: - id: GO:0005829 label: cytosol supported_by: - reference_id: PMID:17329248 supporting_text: >- We mapped the XAP2 binding site to the GAF-B domain of PDE2A. proposed_new_terms: [] suggested_questions: - question: Does the PMID:14557246 aggregation-suppression and mitochondrial preprotein-import evidence warrant annotating AIP to a future general holdase chaperone activity or carrier-holdase term, or should it remain supporting evidence for mitochondrial preprotein import rather than a core molecular function? - question: Should the PN-supported co-chaperone projection for AIP be represented as broad GO:0031072 heat shock protein binding, or should GO curation prefer the more specific GO:0051879 Hsp90 protein binding already proposed in the GO:0051082 replacement reviews? suggested_experiments: [] references: - id: GO_REF:0000002 title: Gene Ontology annotation through association of InterPro records with GO terms findings: [] - id: GO_REF:0000044 title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt findings: [] - id: GO_REF:0000052 title: Gene Ontology annotation based on curation of immunofluorescence data findings: [] - id: GO_REF:0000107 title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara findings: [] - id: GO_REF:0000108 title: Automatic assignment of GO terms using logical inference, based on on inter-ontology links findings: [] - id: GO_REF:0000117 title: Electronic Gene Ontology annotations created by ARBA machine learning models findings: [] - id: PMID:14557246 title: AIP is a mitochondrial import mediator that binds to both import receptor Tom20 and preproteins. findings: [] - id: PMID:17329248 title: Phosphodiesterase 2A forms a complex with the co-chaperone XAP2 and regulates nuclear translocation of the aryl hydrocarbon receptor. findings: [] - id: PMID:19375531 title: XAP2 inhibits glucocorticoid receptor activity in mammalian cells. findings: [] - id: PMID:20029029 title: Regulation of epidermal growth factor receptor trafficking by lysine deacetylase HDAC6. findings: [] - id: PMID:21170051 title: Mixed Hsp90-cochaperone complexes are important for the progression of the reaction cycle. findings: [] - id: PMID:21903422 title: Mapping a dynamic innate immunity protein interaction network regulating type I interferon production. findings: [] - id: PMID:22113938 title: A bead-based approach for large-scale identification of in vitro kinase substrates. findings: [] - id: PMID:23300914 title: 'Structure of the TPR domain of AIP: lack of client protein interaction with the C-terminal α-7 helix of the TPR domain of AIP is sufficient for pituitary adenoma predisposition.' findings: [] - id: PMID:25036637 title: A quantitative chaperone interaction network reveals the architecture of cellular protein homeostasis pathways. findings: [] - id: PMID:28514442 title: Architecture of the human interactome defines protein communities and disease networks. findings: [] - id: PMID:28634279 title: In-frame seven amino-acid duplication in AIP arose over the last 3000 years, disrupts protein interaction and stability and is associated with gigantism. findings: [] - id: PMID:31980649 title: Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRAS(G13D). findings: [] - id: PMID:33961781 title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. findings: [] - id: PMID:35271311 title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.' findings: [] - id: PMID:8972861 title: XAP2, a novel hepatitis B virus X-associated protein that inhibits X transactivation. findings: [] - id: PMID:9447995 title: Hepatitis B virus X-associated protein 2 is a subunit of the unliganded aryl hydrocarbon receptor core complex and exhibits transcriptional enhancer activity. findings: [] - id: Reactome:R-HSA-8936849 title: AHR:2xHSP90:AIP:PTGES3 binds TCDD findings: [] - id: Reactome:R-HSA-8937169 title: AHR:TCDD:2xHSP90AB1:AIP:PTGES3 translocates from cytosol to nucleoplasm findings: [] - id: Reactome:R-HSA-8937191 title: AHR:TCDD:2xHSP90AB1:AIP:PTGES3 dissociates findings: [] - id: Reactome:R-HSA-8950201 title: Expression of Aryl Hydrocarbon receptor-interacting protein findings: [] - id: DOI:10.1038/s41467-022-34773-w title: Cryo-EM structure of the agonist-bound Hsp90-XAP2-AHR cytosolic complex findings: - statement: >- High-resolution cryo-EM structure of the human agonist-bound AHR cytosolic complex with Hsp90 and XAP2/AIP reveals AIP acting as a structural brace associated with the Hsp90 dimer and the AHR client; the Hsp90 C-terminal MEEVD motif docks into the TPR domain of AIP, consistent with canonical TPR-mediated recruitment of HSP90 co-chaperones. - id: DOI:10.18632/oncotarget.24183 title: Multi-chaperone function modulation and association with cytoskeletal proteins are key features of the function of AIP in the pituitary gland findings: - statement: >- Proteomic analysis shows AIP co-localizes with HSPA9 in the mitochondrial chaperone network, consistent with broader chaperone-network associations beyond the AHR complex. - id: DOI:10.1586/eem.10.42 title: Role of the aryl hydrocarbon receptor-interacting protein in familial isolated pituitary adenoma findings: - statement: >- AIP interacts with phosphodiesterases PDE4A5 and PDE2A3, linking it to localized cAMP regulation and potentially to modulation of AHR nuclear translocation and pituitary tumor biology. - id: DOI:10.1038/s41574-023-00948-8 title: "Consensus guideline for the diagnosis and management of pituitary adenomas in childhood and adolescence: Part 1, general recommendations" findings: - statement: >- Among childhood-onset GH-secreting pituitary tumours presenting as gigantism, AIP mutations account for approximately 29% of cases; for macroprolactinomas presenting before age 20, the genetic aetiology includes approximately 9% AIP and 5% MEN1. - id: DOI:10.1093/ejendo/lvad148 title: Genetic testing in prolactinomas - a cohort study findings: - statement: >- In sporadic isolated macroprolactinomas diagnosed at age 30 or younger, the germline pathogenic/likely pathogenic variant prevalence was 4.3% overall, with 1.9% AIP; sporadic macroprolactinoma diagnosed before age 18 had approximately 9-fold higher odds of carrying a germline mutation than diagnosis at 18-30. - id: DOI:10.3389/fendo.2023.1098367 title: AIP gene germline variants in adult Polish patients with apparently sporadic pituitary macroadenomas findings: - statement: >- Penetrance among AIP variant carriers is incomplete and variable, with reported estimates ranging from approximately 12-30%, and some variants/families as low as approximately 6%. - id: file:human/AIP/AIP-deep-research-falcon.md title: Falcon deep research for human AIP findings: - statement: >- Falcon synthesis supports AIP as a cytosolic HSP90/AHR co-chaperone and scaffold that stabilizes client-protein complexes and lacks PPIase catalytic activity. - id: file:projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv title: Proteostasis PN projected gene-GO summary findings: - statement: >- PN projection reports AIP to GO:0031072 heat shock protein binding through the HSP70-HSP90 joint co-chaperone branch and to GO:0003755 peptidyl-prolyl cis-trans isomerase activity through the FKBP-type PPIase branch.