id: Q14318
gene_symbol: FKBP8
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: FKBP8 (FKBP38) is a membrane-anchored member of the FKBP immunophilin family. It has a single FKBP-type peptidyl-prolyl cis-trans isomerase (PPIase) domain, three tetratricopeptide (TPR) repeats, and a C-terminal transmembrane helix that anchors it as a tail-anchored, single-pass protein in the mitochondrial outer membrane with its catalytic domain facing the cytoplasm. Unlike other FKBPs, its PPIase activity is constitutively inactive and is switched on by binding calmodulin in a Ca2+-dependent manner. FKBP8 acts as a chaperone that recruits the anti-apoptotic protein BCL2 to mitochondria and modulates its phosphorylation, thereby regulating apoptosis, and it functions as a mitophagy receptor/adaptor that engages BNIP3 and the LC3/GABARAP autophagy machinery to promote selective clearance of mitochondria. It also contributes to chaperone relays (e.g. axonemal dynein assembly), restricts influenza A virus infection, binds HSP90, and has been implicated in mTOR and Hedgehog/Smoothened signaling. It is regulated by PRKN-mediated ubiquitination (degraded during mitophagy) and USP30 deubiquitination.
existing_annotations:
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic (IBA) annotation of a cytosolic site of action. FKBP8 is a tail-anchored mitochondrial outer-membrane protein with its functional domains facing the cytoplasm/cytosol, so a cytosolic-side site of action is reasonable.
    action: KEEP_AS_NON_CORE
    reason: FKBP8's catalytic and TPR domains face the cytosol, but the protein is membrane-anchored; the mitochondrial membrane is the more precise principal localization. Retained as non-core.
    supported_by:
    - reference_id: file:human/FKBP8/FKBP8-uniprot.txt
      supporting_text: Cytoplasmic side
- term:
    id: GO:0012505
    label: endomembrane system
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic (IBA) annotation placing FKBP8 in the endomembrane system, consistent with its membrane-anchored localization (mitochondrial outer membrane and, by transfer, ER membrane).
    action: KEEP_AS_NON_CORE
    reason: A generic membrane-system localization; the precise mitochondrial outer-membrane annotation is more informative. Retained as non-core.
    supported_by:
    - reference_id: file:human/FKBP8/FKBP8-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion'
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic (IBA) annotation that FKBP8 acts at a membrane, consistent with its C-terminal transmembrane anchor.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the mitochondrial outer-membrane annotation is the more precise localization. Retained as non-core.
    supported_by:
    - reference_id: file:human/FKBP8/FKBP8-uniprot.txt
      supporting_text: Single-pass membrane protein
- term:
    id: GO:0005740
    label: mitochondrial envelope
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic (IBA) annotation placing FKBP8 in the mitochondrial envelope, consistent with its experimentally documented mitochondrial outer-membrane localization.
    action: ACCEPT
    reason: FKBP8 is a tail-anchored mitochondrial outer-membrane (envelope) protein; this localization is experimentally supported and is the principal site of action.
    supported_by:
    - reference_id: file:human/FKBP8/FKBP8-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion'
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic (IBA) annotation of protein folding. FKBP8 has a (conditionally active) PPIase domain and chaperone activity; the molecular function (chaperone / PPIase) is more informative.
    action: KEEP_AS_NON_CORE
    reason: A downstream/contributory process; the chaperone and PPIase molecular functions are the core.
    supported_by:
    - reference_id: file:human/FKBP8/FKBP8-uniprot.txt
      supporting_text: Seems to act as a chaperone for BCL2
- term:
    id: GO:0043066
    label: negative regulation of apoptotic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: FKBP8 chaperones the anti-apoptotic protein BCL2 to mitochondria and modulates its phosphorylation; its active form regulates apoptosis. A plausible biological process for FKBP8.
    action: KEEP_AS_NON_CORE
    reason: FKBP8 modulates apoptosis via BCL2, but the effect can be context-dependent (the BCL2/FKBP8/CaM complex can interfere with BCL2 target binding); retained as a non-core process.
    supported_by:
    - reference_id: file:human/FKBP8/FKBP8-uniprot.txt
      supporting_text: The active form of FKBP8 may therefore play a role in the regulation of apoptosis.
- term:
    id: GO:0044183
    label: protein folding chaperone
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: FKBP8 acts as a chaperone (e.g. for BCL2 and in chaperone relays such as axonemal dynein assembly). A core molecular function.
    action: ACCEPT
    reason: Chaperone function is experimentally supported (BCL2 chaperone; ZMYND10/dynein chaperone relay, IMP PMID:29916806) and inferred phylogenetically; core to FKBP8.
    supported_by:
    - reference_id: file:human/FKBP8/FKBP8-uniprot.txt
      supporting_text: Seems to act as a chaperone for BCL2
- term:
    id: GO:0003755
    label: peptidyl-prolyl cis-trans isomerase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: FKBP8 has an FKBP-type PPIase domain (EC 5.2.1.8), but the activity is constitutively inactive and only switched on by calmodulin/Ca2+ binding. A conditional core molecular function.
    action: ACCEPT
    reason: PPIase activity is documented (EC 5.2.1.8; PubMed:15990872) but is Ca2+/calmodulin-dependent; the IEA correctly reflects the catalytic capacity of the FKBP domain.
    supported_by:
    - reference_id: file:human/FKBP8/FKBP8-uniprot.txt
      supporting_text: Constitutively inactive PPiase, which becomes active when bound to calmodulin and calcium.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Electronic annotation of mitochondrial localization, consistent with the experimentally documented mitochondrial outer-membrane localization.
    action: ACCEPT
    reason: Correct principal localization; agrees with EXP/IDA evidence.
    supported_by:
    - reference_id: file:human/FKBP8/FKBP8-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion'
- term:
    id: GO:0007165
    label: signal transduction
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: Generic electronic annotation of signal transduction. FKBP8 has documented signaling roles (mTOR inhibition, Hedgehog/Smoothened, anti-viral), but the term is non-specific.
    action: KEEP_AS_NON_CORE
    reason: A generic process term; FKBP8's specific signaling roles are better captured elsewhere. Retained as non-core.
    supported_by:
    - reference_id: file:human/FKBP8/FKBP8-goa.tsv
      supporting_text: GO:0007165 signal transduction IEA GO_REF:0000117
- term:
    id: GO:0031966
    label: mitochondrial membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic annotation of mitochondrial membrane localization, consistent with FKBP8's tail-anchored mitochondrial outer-membrane localization.
    action: ACCEPT
    reason: Correct principal localization (single-pass mitochondrial outer-membrane protein); agrees with EXP evidence.
    supported_by:
    - reference_id: file:human/FKBP8/FKBP8-uniprot.txt
      supporting_text: Mitochondrion membrane
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16844119
  qualifier: enables
  review:
    summary: Interaction with hepatitis C virus NS5A (O39474). Bare protein binding is uninformative; a microbial-infection interaction.
    action: KEEP_AS_NON_CORE
    reason: A real virus-host interaction documented in UniProt, but recorded as bare protein binding and peripheral to the core function.
    supported_by:
    - reference_id: file:human/FKBP8/FKBP8-uniprot.txt
      supporting_text: Interacts with hepatitis C/HCV protein NS5A.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17024179
  qualifier: enables
  review:
    summary: IntAct interactions with HCV NS5A (O39474) and HSP90AA1 (P07900). Bare protein binding is uninformative; the HSP90 interaction is the most informative.
    action: MODIFY
    reason: Bare protein binding is uninformative; the WITH partner HSP90AA1 makes Hsp90 protein binding (GO:0051879) the precise function.
    proposed_replacement_terms:
    - id: GO:0051879
      label: Hsp90 protein binding
    supported_by:
    - reference_id: file:human/FKBP8/FKBP8-goa.tsv
      supporting_text: GO:0005515 protein binding IPI PMID:17024179 UniProtKB:P07900
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17082457
  qualifier: enables
  review:
    summary: IntAct interaction with ZFYVE27/protrudin (Q5T4F4). Bare protein binding is uninformative; FKBP8 may negatively regulate ZFYVE27 phosphorylation.
    action: KEEP_AS_NON_CORE
    reason: A real, specific interaction (ZFYVE27) documented in UniProt, but recorded as bare protein binding and not the core function.
    supported_by:
    - reference_id: file:human/FKBP8/FKBP8-uniprot.txt
      supporting_text: Interacts with ZFYVE27
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17353276
  qualifier: enables
  review:
    summary: IntAct interaction with EGLN1/PHD2 (Q9GZT9). Bare protein binding is uninformative; an isolated interactome hit.
    action: KEEP_AS_NON_CORE
    reason: An isolated interaction recorded as bare protein binding; uninformative and not core.
    supported_by:
    - reference_id: file:human/FKBP8/FKBP8-goa.tsv
      supporting_text: GO:0005515 protein binding IPI PMID:17353276 UniProtKB:Q9GZT9
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18216108
  qualifier: enables
  review:
    summary: IntAct interaction with a viral protein (Q9WMX2 processed chain). Bare protein binding is uninformative; a virus-host interaction.
    action: KEEP_AS_NON_CORE
    reason: A virus-host interaction recorded as bare protein binding; not part of the core function.
    supported_by:
    - reference_id: file:human/FKBP8/FKBP8-goa.tsv
      supporting_text: GO:0005515 protein binding IPI PMID:18216108 UniProtKB:Q9WMX2-PRO_0000037551
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18459960
  qualifier: enables
  review:
    summary: IntAct interaction with ZFYVE27/protrudin (Q5T4F4). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: A real, specific interaction (ZFYVE27) recorded as bare protein binding; not the core function.
    supported_by:
    - reference_id: file:human/FKBP8/FKBP8-uniprot.txt
      supporting_text: Interacts with ZFYVE27
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20029029
  qualifier: enables
  review:
    summary: IntAct interaction with EGFR (P00533). Bare protein binding is uninformative; an isolated interactome hit.
    action: KEEP_AS_NON_CORE
    reason: An isolated interaction recorded as bare protein binding; uninformative and not core.
    supported_by:
    - reference_id: file:human/FKBP8/FKBP8-goa.tsv
      supporting_text: GO:0005515 protein binding IPI PMID:20029029 UniProtKB:P00533
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21360678
  qualifier: enables
  review:
    summary: IntAct interaction with HSP90AA1 (P07900). Bare protein binding is uninformative; the partner is HSP90.
    action: MODIFY
    reason: Bare protein binding is uninformative; the WITH partner is HSP90AA1, so Hsp90 protein binding (GO:0051879) is the precise function.
    proposed_replacement_terms:
    - id: GO:0051879
      label: Hsp90 protein binding
    supported_by:
    - reference_id: file:human/FKBP8/FKBP8-goa.tsv
      supporting_text: GO:0005515 protein binding IPI PMID:21360678 UniProtKB:P07900
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24169621
  qualifier: enables
  review:
    summary: IntAct interaction with a viral protein (Q9WMX2 processed chain). Bare protein binding is uninformative; a virus-host interaction.
    action: KEEP_AS_NON_CORE
    reason: A virus-host interaction recorded as bare protein binding; not part of the core function.
    supported_by:
    - reference_id: file:human/FKBP8/FKBP8-goa.tsv
      supporting_text: GO:0005515 protein binding IPI PMID:24169621 UniProtKB:Q9WMX2-PRO_0000037551
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25036637
  qualifier: enables
  review:
    summary: Quantitative chaperone interaction network (Taipale et al.) capturing FKBP8-HSP90AB1 (P08238). Bare protein binding is uninformative; the partner is HSP90.
    action: MODIFY
    reason: Bare protein binding is uninformative; the WITH partner is HSP90AB1, so Hsp90 protein binding (GO:0051879) is the precise function.
    proposed_replacement_terms:
    - id: GO:0051879
      label: Hsp90 protein binding
    supported_by:
    - reference_id: file:human/FKBP8/FKBP8-goa.tsv
      supporting_text: GO:0005515 protein binding IPI PMID:25036637 UniProtKB:P08238
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26567527
  qualifier: enables
  review:
    summary: IntAct interactions with FKBP6 (O75344) and a viral protein. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real interactions recorded as bare protein binding; not individually core.
    supported_by:
    - reference_id: file:human/FKBP8/FKBP8-goa.tsv
      supporting_text: GO:0005515 protein binding IPI PMID:26567527 UniProtKB:O75344
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28169297
  qualifier: enables
  review:
    summary: IntAct interactions with influenza A virus PB1 proteins (P03431, Q5EP37). Bare protein binding is uninformative; FKBP8 restricts influenza A virus infection.
    action: KEEP_AS_NON_CORE
    reason: A real virus-host interaction (IAV PB1) recorded as bare protein binding; relevant to FKBP8's anti-viral role but not a core MF annotation.
    supported_by:
    - reference_id: file:human/FKBP8/FKBP8-goa.tsv
      supporting_text: GO:0005515 protein binding IPI PMID:28169297 UniProtKB:P03431
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31980649
  qualifier: enables
  review:
    summary: IntAct interaction with EGFR (P00533). Bare protein binding is uninformative; an isolated interactome hit.
    action: KEEP_AS_NON_CORE
    reason: An isolated interaction recorded as bare protein binding; uninformative and not core.
    supported_by:
    - reference_id: file:human/FKBP8/FKBP8-goa.tsv
      supporting_text: GO:0005515 protein binding IPI PMID:31980649 UniProtKB:P00533
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: A large membrane-protein interactome screen reporting ~25 FKBP8 partners, almost all single-pass transmembrane/membrane proteins. Bare protein binding from a broad screen of a membrane-anchored bait is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Bare protein binding from one high-throughput membrane-interactome screen with many partners not independently validated; uninformative and not reflective of the core function.
    supported_by:
    - reference_id: file:human/FKBP8/FKBP8-goa.tsv
      supporting_text: GO:0005515 protein binding IPI PMID:32296183 UniProtKB:P10415
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35271311
  qualifier: enables
  review:
    summary: A high-throughput screen capturing FKBP8 with HSP90AA1/AB1 (P07900/P08238). The HSP90 interactions are the most informative.
    action: MODIFY
    reason: Bare protein binding is uninformative; the partners include HSP90AA1/AB1, so Hsp90 protein binding (GO:0051879) is appropriate.
    proposed_replacement_terms:
    - id: GO:0051879
      label: Hsp90 protein binding
    supported_by:
    - reference_id: file:human/FKBP8/FKBP8-goa.tsv
      supporting_text: GO:0005515 protein binding IPI PMID:35271311 UniProtKB:P07900
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:17024179
  qualifier: enables
  review:
    summary: FKBP8 self-interaction (Q14318-Q14318), consistent with the documented ability to form homomultimers.
    action: KEEP_AS_NON_CORE
    reason: A real self-association (homomultimer), but a generic binding term peripheral to FKBP8's core chaperone/PPIase function.
    supported_by:
    - reference_id: file:human/FKBP8/FKBP8-uniprot.txt
      supporting_text: Homomultimers or heteromultimers
- term:
    id: GO:0005740
    label: mitochondrial envelope
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Electronic annotation (from mouse O35465) of mitochondrial envelope localization, consistent with the experimentally documented mitochondrial outer-membrane localization.
    action: ACCEPT
    reason: Correct principal localization; agrees with EXP/IDA evidence.
    supported_by:
    - reference_id: file:human/FKBP8/FKBP8-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion'
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Electronic annotation (from mouse O35465) of ER membrane localization. A secondary membrane compartment for this tail-anchored protein, not the principal characterized location.
    action: KEEP_AS_NON_CORE
    reason: Plausible secondary localization of a tail-anchored protein, transferred electronically from mouse; the mitochondrial outer membrane is the principal site. Retained as non-core.
    supported_by:
    - reference_id: file:human/FKBP8/FKBP8-goa.tsv
      supporting_text: GO:0005789 endoplasmic reticulum membrane IEA GO_REF:0000107 UniProtKB:O35465
- term:
    id: GO:0044183
    label: protein folding chaperone
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Electronic annotation (from mouse O35465) of chaperone activity, consistent with the experimentally documented chaperone function (BCL2 chaperone; dynein assembly relay).
    action: ACCEPT
    reason: Agrees with experimental chaperone evidence; a core molecular function.
    supported_by:
    - reference_id: file:human/FKBP8/FKBP8-uniprot.txt
      supporting_text: Seems to act as a chaperone for BCL2
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32686675
  qualifier: enables
  review:
    summary: IntAct interaction (Q8NEN9/DIP2B). Bare protein binding is uninformative; an isolated interactome hit.
    action: KEEP_AS_NON_CORE
    reason: An isolated interaction recorded as bare protein binding; uninformative and not core.
    supported_by:
    - reference_id: file:human/FKBP8/FKBP8-goa.tsv
      supporting_text: GO:0005515 protein binding IPI PMID:32686675 UniProtKB:Q8NEN9
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Direct immunofluorescence (HPA) evidence for mitochondrial localization, the principal site of FKBP8 action.
    action: ACCEPT
    reason: IDA-supported mitochondrial localization agrees with the documented principal site.
    supported_by:
    - reference_id: file:human/FKBP8/FKBP8-goa.tsv
      supporting_text: GO:0005739 mitochondrion IDA GO_REF:0000052
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: EXP
  original_reference_id: PMID:16176796
  qualifier: located_in
  review:
    summary: Experimental evidence for mitochondrial localization of FKBP8.
    action: ACCEPT
    reason: Directly experimentally supported principal localization.
    supported_by:
    - reference_id: file:human/FKBP8/FKBP8-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion'
- term:
    id: GO:0031966
    label: mitochondrial membrane
  evidence_type: EXP
  original_reference_id: PMID:12510191
  qualifier: located_in
  review:
    summary: Experimental evidence for FKBP8 localization to the mitochondrial membrane (single-pass, cytoplasmic side).
    action: ACCEPT
    reason: Directly experimentally supported principal localization as a tail-anchored mitochondrial outer-membrane protein.
    supported_by:
    - reference_id: file:human/FKBP8/FKBP8-uniprot.txt
      supporting_text: Mitochondrion membrane
- term:
    id: GO:0031966
    label: mitochondrial membrane
  evidence_type: EXP
  original_reference_id: PMID:18385096
  qualifier: located_in
  review:
    summary: Experimental evidence (isoform-resolved) for FKBP8 localization to the mitochondrial membrane.
    action: ACCEPT
    reason: Directly experimentally supported principal localization.
    supported_by:
    - reference_id: file:human/FKBP8/FKBP8-uniprot.txt
      supporting_text: Mitochondrion membrane
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: High-throughput evidence for mitochondrial localization, consistent with the principal site of FKBP8 action.
    action: ACCEPT
    reason: Consistent with strong EXP/IDA evidence for mitochondrial localization.
    supported_by:
    - reference_id: file:human/FKBP8/FKBP8-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion'
- term:
    id: GO:1901524
    label: regulation of mitophagy
  evidence_type: IDA
  original_reference_id: PMID:28381481
  qualifier: involved_in
  review:
    summary: Direct evidence that FKBP8 regulates mitophagy, acting as a mitophagy receptor/adaptor that engages BNIP3 and the LC3/GABARAP autophagy machinery. A core biological process.
    action: ACCEPT
    reason: Directly demonstrated (IDA) role in regulation of mitophagy; FKBP8 is a recognized mitophagy receptor.
    supported_by:
    - reference_id: file:human/FKBP8/FKBP8-goa.tsv
      supporting_text: GO:1901524 regulation of mitophagy IDA PMID:28381481
- term:
    id: GO:1901524
    label: regulation of mitophagy
  evidence_type: IDA
  original_reference_id: PMID:31908024
  qualifier: involved_in
  review:
    summary: Second direct demonstration that FKBP8 regulates mitophagy. A core biological process.
    action: ACCEPT
    reason: Independently corroborated (IDA) role in regulation of mitophagy.
    supported_by:
    - reference_id: file:human/FKBP8/FKBP8-goa.tsv
      supporting_text: GO:1901524 regulation of mitophagy IDA PMID:31908024
- term:
    id: GO:0070585
    label: protein localization to mitochondrion
  evidence_type: IPI
  original_reference_id: PMID:31908024
  qualifier: involved_in
  review:
    summary: FKBP8 promotes protein localization to mitochondria (WITH partner BNIP3, Q9GZQ8), consistent with its mitophagy-receptor/adaptor role.
    action: ACCEPT
    reason: Supported by direct interaction evidence; consistent with FKBP8's documented role in targeting proteins (e.g. BCL2, BNIP3) to mitochondria.
    supported_by:
    - reference_id: file:human/FKBP8/FKBP8-goa.tsv
      supporting_text: GO:0070585 protein localization to mitochondrion IPI PMID:31908024 UniProtKB:Q9GZQ8
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28381481
  qualifier: enables
  review:
    summary: IntAct interactions with autophagy LC3/GABARAP family proteins and BNIP3 (Q9GZQ8), underlying FKBP8's mitophagy-receptor function. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real, biologically meaningful interactions (autophagy machinery/BNIP3), but recorded as bare protein binding; the mitophagy function is captured by the dedicated process terms.
    supported_by:
    - reference_id: file:human/FKBP8/FKBP8-goa.tsv
      supporting_text: GO:0005515 protein binding IPI PMID:28381481 UniProtKB:O95166
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31908024
  qualifier: enables
  review:
    summary: IntAct interaction with BNIP3 (Q9GZQ8), underlying FKBP8's mitophagy-receptor function. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: A real, biologically meaningful interaction (BNIP3) recorded as bare protein binding; the mitophagy function is captured by the dedicated process terms.
    supported_by:
    - reference_id: file:human/FKBP8/FKBP8-goa.tsv
      supporting_text: GO:0005515 protein binding IPI PMID:31908024 UniProtKB:Q9GZQ8
- term:
    id: GO:0005516
    label: calmodulin binding
  evidence_type: EXP
  original_reference_id: PMID:20707607
  qualifier: enables
  review:
    summary: FKBP8 binds calmodulin; calmodulin/Ca2+ binding activates its otherwise-inactive PPIase domain. A core molecular function.
    action: ACCEPT
    reason: Calmodulin binding is experimentally demonstrated and is the switch that activates FKBP8's catalytic and BCL2-chaperone activity; central to its regulation.
    supported_by:
    - reference_id: file:human/FKBP8/FKBP8-uniprot.txt
      supporting_text: Forms heterodimer with calmodulin.
- term:
    id: GO:0005516
    label: calmodulin binding
  evidence_type: IPI
  original_reference_id: PMID:24145868
  qualifier: enables
  review:
    summary: Interaction with calmodulin (P0DP23) confirmed by IPI. A core molecular function.
    action: ACCEPT
    reason: Calmodulin binding is the activating interaction for FKBP8's PPIase and chaperone activities.
    supported_by:
    - reference_id: file:human/FKBP8/FKBP8-goa.tsv
      supporting_text: GO:0005516 calmodulin binding IPI PMID:24145868 UniProtKB:P0DP23
- term:
    id: GO:0005516
    label: calmodulin binding
  evidence_type: EXP
  original_reference_id: PMID:24145868
  qualifier: enables
  review:
    summary: Experimental confirmation of FKBP8-calmodulin binding. A core molecular function.
    action: ACCEPT
    reason: Independently corroborates the activating calmodulin interaction.
    supported_by:
    - reference_id: file:human/FKBP8/FKBP8-uniprot.txt
      supporting_text: Forms heterodimer with calmodulin.
- term:
    id: GO:0006457
    label: protein folding
  evidence_type: IMP
  original_reference_id: PMID:29916806
  qualifier: acts_upstream_of_or_within
  review:
    summary: FKBP8 functions in a chaperone relay during axonemal dynein assembly (ZMYND10 study). The chaperone molecular function is the more informative annotation; folding is the process context.
    action: KEEP_AS_NON_CORE
    reason: A genuine chaperone-relay folding role (IMP), but the chaperone MF is the core; folding is retained as a non-core process.
    supported_by:
    - reference_id: file:human/FKBP8/FKBP8-goa.tsv
      supporting_text: GO:0006457 protein folding IMP PMID:29916806
- term:
    id: GO:0044183
    label: protein folding chaperone
  evidence_type: IMP
  original_reference_id: PMID:29916806
  qualifier: enables
  review:
    summary: FKBP8 acts as a chaperone in the ZMYND10-dependent chaperone relay for axonemal dynein assembly (IMP). A core molecular function.
    action: ACCEPT
    reason: Mutant-phenotype evidence supports FKBP8's chaperone function in dynein assembly, corroborating the chaperone MF.
    supported_by:
    - reference_id: file:human/FKBP8/FKBP8-goa.tsv
      supporting_text: GO:0044183 protein folding chaperone IMP PMID:29916806
- term:
    id: GO:0001933
    label: negative regulation of protein phosphorylation
  evidence_type: IMP
  original_reference_id: PMID:15733859
  qualifier: involved_in
  review:
    summary: FKBP8 modulates the phosphorylation state of BCL2 (and ZFYVE27); the BCL2 flexible loop mediates the FKBP8 interaction. A plausible process linked to its chaperone role.
    action: KEEP_AS_NON_CORE
    reason: A real but specialized process (BCL2 phospho modulation); retained as non-core relative to the core chaperone/mitophagy functions.
    supported_by:
    - reference_id: PMID:15733859
      supporting_text: flexible loop of Bcl-2 is required for molecular interaction
- term:
    id: GO:0032991
    label: protein-containing complex
  evidence_type: IMP
  original_reference_id: PMID:15733859
  qualifier: part_of
  review:
    summary: FKBP8 is part of a BCL2-containing complex (BCL2/FKBP8/calmodulin/Ca2+). A generic complex-membership annotation.
    action: KEEP_AS_NON_CORE
    reason: A generic protein-complex term; the specific BCL2/calmodulin interactions are captured elsewhere. Retained as non-core.
    supported_by:
    - reference_id: file:human/FKBP8/FKBP8-uniprot.txt
      supporting_text: The BCL2/FKBP8/calmodulin/calcium complex probably interferes with the binding of BCL2 to its targets.
- term:
    id: GO:0097718
    label: disordered domain specific binding
  evidence_type: IPI
  original_reference_id: PMID:15733859
  qualifier: enables
  review:
    summary: FKBP8 binds the disordered flexible loop of BCL2 (P10415). A specific molecular function capturing the BCL2-chaperone interaction mode.
    action: ACCEPT
    reason: Directly supported (IPI) binding to the disordered flexible loop of BCL2; an informative molecular function underlying the BCL2-chaperone role.
    supported_by:
    - reference_id: PMID:15733859
      supporting_text: flexible loop of Bcl-2 is required for molecular interaction
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18160438
  qualifier: enables
  review:
    summary: IntAct interaction (Q9P035/HACD3). Bare protein binding is uninformative; an isolated interactome hit.
    action: KEEP_AS_NON_CORE
    reason: An isolated interaction recorded as bare protein binding; uninformative and not core.
    supported_by:
    - reference_id: file:human/FKBP8/FKBP8-goa.tsv
      supporting_text: GO:0005515 protein binding IPI PMID:18160438 UniProtKB:Q9P035
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: High-throughput proteomic detection of FKBP8 in a membrane fraction, consistent with its membrane-anchored nature.
    action: KEEP_AS_NON_CORE
    reason: A generic membrane localization from proteomics; the mitochondrial outer-membrane annotation is more precise. Retained as non-core.
    supported_by:
    - reference_id: file:human/FKBP8/FKBP8-uniprot.txt
      supporting_text: Single-pass membrane protein
- term:
    id: GO:0035556
    label: intracellular signal transduction
  evidence_type: TAS
  original_reference_id: PMID:10197430
  qualifier: involved_in
  review:
    summary: Author-stated involvement in intracellular signal transduction. FKBP8 has documented signaling roles (mTOR, Hedgehog), but the term is non-specific.
    action: KEEP_AS_NON_CORE
    reason: A generic signaling process term; FKBP8's specific signaling roles are better captured elsewhere. Retained as non-core.
    supported_by:
    - reference_id: file:human/FKBP8/FKBP8-goa.tsv
      supporting_text: GO:0035556 intracellular signal transduction TAS PMID:10197430
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation through association of InterPro records with GO terms
  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:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10197430
  title: 'muFKBP38: a novel murine immunophilin homolog differentially expressed in Schwannoma cells and central nervous system neurons in vivo.'
  findings: []
- id: PMID:12510191
  title: 'Inherent calcineurin inhibitor FKBP38 targets Bcl-2 to mitochondria and inhibits apoptosis.'
  findings:
  - statement: FKBP38 localizes to the mitochondrial membrane and targets BCL2 to mitochondria.
    reference_section_type: RESULTS
- id: PMID:15733859
  title: The flexible loop of Bcl-2 is required for molecular interaction with immunosuppressant FK-506 binding protein 38 (FKBP38).
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: "Cached publications/PMID_15733859.md title matches YAML; establishes the FKBP8(FKBP38)-BCL2 interaction underlying the BCL2-chaperone core function. GOA also anchors this PMID to GO:0001933 (IMP) and GO:0032991 (protein complex)."
  findings:
  - statement: The disordered flexible loop of BCL2 mediates its interaction with FKBP38, which modulates BCL2 phosphorylation.
    reference_section_type: RESULTS
- id: PMID:16176796
  title: 'Molecular characterization of FK-506 binding protein 38 and its potential regulatory role on the anti-apoptotic protein Bcl-2.'
  findings:
  - statement: FKBP38 localizes to mitochondria.
    reference_section_type: RESULTS
- id: PMID:16844119
  title: 'Hepatitis C virus non-structural protein NS5A interacts with FKBP38 and inhibits apoptosis in Huh7 hepatoma cells.'
  findings: []
- id: PMID:17024179
  title: 'Hepatitis C virus RNA replication is regulated by FKBP8 and Hsp90.'
  findings: []
- id: PMID:17082457
  title: Protrudin induces neurite formation by directional membrane trafficking.
  findings: []
- id: PMID:17353276
  title: The peptidyl prolyl cis/trans isomerase FKBP38 determines hypoxia-inducible transcription factor prolyl-4-hydroxylase PHD2 protein stability.
  findings: []
- id: PMID:18160438
  title: Human butyrate-induced transcript 1 interacts with hepatitis C virus NS5A and regulates viral replication.
  findings: []
- id: PMID:18216108
  title: A single-amino-acid mutation in hepatitis C virus NS5A disrupting FKBP8 interaction impairs viral replication.
  findings: []
- id: PMID:18385096
  title: 'Characterization of a Bcl-XL-interacting protein FKBP8 and its splice variant in human RPE cells.'
  findings:
  - statement: FKBP38 isoforms localize to the mitochondrial membrane.
    reference_section_type: RESULTS
- id: PMID:18459960
  title: Regulation of apoptosis and neurite extension by FKBP38 is required for neural tube formation in the mouse.
  findings: []
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
- id: PMID:20029029
  title: Regulation of epidermal growth factor receptor trafficking by lysine deacetylase HDAC6.
  findings: []
- id: PMID:20707607
  title: 'New structural aspects of FKBP38 activation.'
  findings:
  - statement: FKBP38 binds calmodulin; calmodulin/Ca2+ activates its PPIase activity.
    reference_section_type: RESULTS
- id: PMID:21360678
  title: Label-free quantitative proteomics and SAINT analysis enable interactome mapping for the human Ser/Thr protein phosphatase 5.
  findings: []
- id: PMID:24145868
  title: Functional role of the flexible N-terminal extension of FKBP38 in catalysis.
  findings:
  - statement: FKBP38 binds calmodulin.
    reference_section_type: RESULTS
- id: PMID:24169621
  title: Elucidating novel hepatitis C virus-host interactions using combined mass spectrometry and functional genomics approaches.
  findings: []
- id: PMID:25036637
  title: A quantitative chaperone interaction network reveals the architecture of cellular protein homeostasis pathways.
  findings:
  - statement: FKBP8 interacts with HSP90 within the chaperone interaction network.
    reference_section_type: RESULTS
- id: PMID:26567527
  title: 'Involvement of FKBP6 in hepatitis C virus replication.'
  findings: []
- id: PMID:28169297
  title: Comparative influenza protein interactomes identify the role of plakophilin 2 in virus restriction.
  findings:
  - statement: FKBP8 interacts with influenza A virus PB1 and contributes to restriction of viral infection.
    reference_section_type: RESULTS
- id: PMID:28381481
  title: 'FKBP8 recruits LC3A to mediate Parkin-independent mitophagy.'
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: "Not cached, but anchored to GOA: this PMID is an IDA source for GO:1901524 (regulation of mitophagy) in FKBP8-goa.tsv, supporting FKBP8's mitophagy-receptor core function."
  findings:
  - statement: FKBP8 regulates mitophagy, acting as a mitophagy receptor that engages the autophagy machinery.
    reference_section_type: RESULTS
- id: PMID:29916806
  title: ZMYND10 functions in a chaperone relay during axonemal dynein assembly.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: "Cached publications/PMID_29916806.md title matches YAML; body explicitly describes FKBP8 as an HSP90 co-chaperone in a dynein chaperone relay, supporting the core protein-folding chaperone MF. GOA anchors this PMID to GO:0044183 (co-chaperone, IMP) and GO:0006457 (protein folding)."
  findings:
  - statement: FKBP8 functions as a chaperone in a relay (with ZMYND10) during axonemal dynein assembly.
    reference_section_type: RESULTS
- id: PMID:31908024
  title: 'FKBP8 LIRL-dependent mitochondrial fragmentation facilitates mitophagy under stress conditions.'
  findings:
  - statement: FKBP8 regulates mitophagy and promotes protein (BNIP3) localization to mitochondria.
    reference_section_type: RESULTS
- id: PMID:31980649
  title: Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRAS(G13D).
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:32686675
  title: PDZD8 interacts with Protrudin and Rab7 at ER-late endosome membrane contact sites associated with mitochondria.
  findings: []
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.
  findings: []
- id: PMID:35271311
  title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
  findings: []
- id: file:human/FKBP8/FKBP8-uniprot.txt
  title: UniProt entry Q14318 (FKBP8_HUMAN), Peptidyl-prolyl cis-trans isomerase FKBP8 / FKBP38
  findings:
  - statement: Tail-anchored mitochondrial outer-membrane FKBP; constitutively inactive PPIase activated by calmodulin/Ca2+; chaperone for BCL2 (targets it to mitochondria, modulates phosphorylation); mitophagy receptor engaging BNIP3/autophagy machinery; restricts influenza A virus; binds HSP90.
    reference_section_type: OTHER
core_functions:
- description: Calmodulin/Ca2+-activated peptidyl-prolyl cis-trans isomerase; the FKBP-type PPIase domain is constitutively inactive and is switched on by binding calmodulin in a Ca2+-dependent manner.
  molecular_function:
    id: GO:0003755
    label: peptidyl-prolyl cis-trans isomerase activity
  locations:
  - id: GO:0031966
    label: mitochondrial membrane
  supported_by:
  - reference_id: file:human/FKBP8/FKBP8-uniprot.txt
    supporting_text: Constitutively inactive PPiase, which becomes active when bound to calmodulin and calcium.
- description: Membrane-anchored chaperone/adaptor that recruits BCL2 (via its disordered flexible loop) to the mitochondrial outer membrane and modulates BCL2 phosphorylation; also acts in chaperone relays such as axonemal dynein assembly.
  molecular_function:
    id: GO:0044183
    label: protein folding chaperone
  locations:
  - id: GO:0031966
    label: mitochondrial membrane
  supported_by:
  - reference_id: file:human/FKBP8/FKBP8-uniprot.txt
    supporting_text: Seems to act as a chaperone for BCL2
  - reference_id: PMID:15733859
    supporting_text: flexible loop of Bcl-2 is required for molecular interaction
- description: Calmodulin binding, the regulatory interaction that activates FKBP8's PPIase and BCL2-chaperone activities in a Ca2+-dependent manner.
  molecular_function:
    id: GO:0005516
    label: calmodulin binding
  locations:
  - id: GO:0031966
    label: mitochondrial membrane
  supported_by:
  - reference_id: file:human/FKBP8/FKBP8-uniprot.txt
    supporting_text: Forms heterodimer with calmodulin.
- description: Mitophagy receptor/adaptor that engages BNIP3 and the LC3/GABARAP autophagy machinery at the mitochondrial outer membrane to regulate selective mitochondrial clearance.
  molecular_function:
    id: GO:0044183
    label: protein folding chaperone
  locations:
  - id: GO:0031966
    label: mitochondrial membrane
  supported_by:
  - reference_id: file:human/FKBP8/FKBP8-goa.tsv
    supporting_text: GO:1901524 regulation of mitophagy IDA PMID:28381481
proposed_new_terms: []
suggested_questions:
- question: Is FKBP8's Ca2+/calmodulin-activated PPIase catalytic activity required for its BCL2-chaperone and mitophagy-receptor functions, or are these adaptor roles catalysis-independent?
- question: How is FKBP8's dual role as an anti-apoptotic BCL2 chaperone reconciled with its pro-mitophagy receptor function at the same mitochondrial outer membrane?
- question: What determines the partitioning of FKBP8 between the mitochondrial outer membrane and the ER membrane, and does the ER pool have a distinct function?
suggested_experiments:
- description: Test PPIase-dead and calmodulin-binding-deficient FKBP8 mutants for BCL2 mitochondrial targeting, BCL2 phosphorylation, and mitophagy induction to separate catalytic from adaptor contributions.
- description: Use FKBP8 knockout/knockdown with BNIP3- and PRKN-dependent mitophagy reporters to define its role as a mitophagy receptor and its regulation by USP30/PRKN ubiquitination.
- description: Map the FKBP8 interactome by compartment-resolved proximity labeling to distinguish bona fide functional partners (BCL2, BNIP3, calmodulin, HSP90, LC3/GABARAP) from co-fractionating membrane proteins in high-throughput screens.