FNIP1

Summary: FNIP1 participates in suppression of TFE3-dependent transcription in defined cell assays.

Reason: PMID:21209915 measures GPNMB promoter reporters and expression in human cells. FNIP1 expression suppresses TFE3-driven reporter activity in HT1080 cells, while FLCN/FNIP combinations strengthen selected effects; FNIP1 alone does not suppress GPNMB in FLCN-null UOK257 cells. This supports a contextual regulatory contribution through the FLCN–TFE pathway, not DNA binding or general RNA polymerase II repression by FNIP1. Preserve the original TFE3 participant extension and the distinction between promoter response and direct transcription-factor binding.

Summary: FNIP1 supports immature B-cell development through a metabolic and survival checkpoint.

Reason: The exact mouse donor Q68FD7 cites PMID:22608497. Fnip1-deficient mouse B-cell precursors fail to mature efficiently; mixed bone-marrow transplantation supports a cell-intrinsic defect, and re-expression of Fnip1 rescues B-cell development. Nutrient and survival perturbations place this requirement in a metabolic checkpoint rather than a lineage-specifying transcriptional activity. Human FNIP1 deficiency also reduces immature and peripheral B cells (PMID:32905580), but the sampled patient did not show the same overt maturation block as the mouse model. Retain the original ISS as a contextual developmental role.

Summary: The inspected donor experiments support protection from B-cell apoptosis, the opposite regulatory direction.

Reason: The human ISS retains mouse FNIP1 Q68FD7 as its source. The donor GOA assigns the positive term from PMID:22608497, but the actual mouse Results show increased apoptosis after Fnip1 loss under pre-BCR stimulation, nutrient stress and Eμ-Myc expression; Annexin V/viability assays and the Discussion identify normal Fnip1 as supporting survival. PMID:22709692 independently finds increased pre-B-cell death and caspase activity after Fnip1 loss, with Bcl2 rescue. The evidence therefore supports negative regulation of B-cell apoptotic process in these contexts. Propose GO:0002903 while preserving the original positive term, source and ISS provenance; this is a source-direction correction, not a claim of direct caspase inhibition or universal anti-apoptotic activity.

Proposed replacements: negative regulation of B cell apoptotic process

Summary: FNIP1 associates with the regulatory gamma subunit of the AMPK complex.

Reason: PMID:17028174 identifies PRKAG1 in FNIP1-associated material and supports FNIP1–AMPK association. PRKAG1 is the nucleotide-sensing regulatory gamma subunit, not the catalytic alpha subunit. Retain this partner-specific association as non-core under the standing campaign instructions; do not infer protein kinase binding to this individual regulatory chain or a separately measured direct binary interface.

Summary: FNIP1 binds the catalytic protein-kinase subunit of AMPK in an AMPK-associated complex.

Reason: PMID:17028174 supports FNIP1 association with AMPK, including the original PRKAA1 catalytic-alpha partner, and links the complex to phosphorylation of FNIP1. GO:0019901 identifies the established protein-kinase partner class. The source includes co-complex and pulldown evidence and does not assign kinase catalysis to FNIP1 or resolve a purified interface independently of the AMPK regulatory subunits.

Proposed replacements: protein kinase binding

Summary: FNIP1 binds folliculin, a GTPase-activating protein and signaling-complex partner.

Reason: PMID:17028174 establishes FNIP1–FLCN association by endogenous and tagged co-immunoprecipitation and FLCN-domain pulldown experiments. FLCN is the established GAP component of the Rag-regulatory complex; GO:0032794 specifies that partner class without assigning GAP catalysis to FNIP1. The original association is distinct from the unresolved claim that FNIP1 directly increases FLCN catalytic activity. The two source records projecting here remain separately preserved in provenance.

Proposed replacements: GTPase activating protein binding

Summary: FNIP1 associates with the regulatory beta subunit of the AMPK complex.

Reason: PMID:17028174 supports FNIP1 association with AMPK including PRKAB1. This beta chain is a regulatory/scaffolding subunit rather than a catalytic protein kinase. Retain the source-specific complex association as non-core; do not transfer the catalytic-alpha classification to this partner or infer a separately measured binary interface.

Summary: FNIP1 associates with the folliculin GAP component in a regulated protein complex.

Reason: PMID:18403135 reports human FNIP–FLCN complexes using tagged and endogenous interaction assays. GO:0032794 identifies the established FLCN GAP-partner class, with later pathway evidence distinguished from the original binding experiment. This is binding to the GAP component, not independent GAP activity or a measured FNIP1-mediated activation of FLCN catalysis; reported multimer association does not establish a universal stoichiometry.

Proposed replacements: GTPase activating protein binding

Summary: FNIP1 associates with its paralog FNIP2 in cellular and translation-lysate assays.

Reason: PMID:18403135 supports human FNIP1–FNIP2 association by reciprocal endogenous/tagged cellular experiments and GST/reticulocyte-translation capture. Retain this partner-specific oligomeric association as non-core. These assays do not supply purified stoichiometry or a more informative independently demonstrated binding subtype, and the paralog association is not itself evidence that every natural FNIP1 product performs the same function.

Summary: Human FNIP1 associates with rat folliculin in a phosphorylation-linked complex.

Reason: The original partner Q76JQ2 is rat Flcn. Selected publisher-indexed Results and Supplementary Figure S4 caption from PMID:19914239 describe Myc-FNIP1 co-immunoprecipitation of Flag-tagged rat FLCN variants in COS7 cells; binding is retained across S62 substitutions. GO:0032794 specifies the folliculin GAP-partner class without relabeling the assayed protein as human or claiming FNIP1 catalysis. The normal cache remains abstract-only, and neither the supplementary image nor complete original Methods were inspected.

Proposed replacements: GTPase activating protein binding

Summary: FNIP1 associates with the ubiquitin-like ATG8-family protein GABARAP.

Reason: PMID:20562859 has exact target-specific interaction records for FNIP1 and GABARAP. The records distinguish tagged cellular co-immunoprecipitation from the GABARAPL1 GST/radiolabeled-FNIP1 pulldown. Both partners are ATG8-family ubiquitin-like conjugating proteins, so GO:0032182 preserves the informative partner class. This does not make FNIP1 a ubiquitin-conjugating enzyme or establish a cargo-adaptor function from association alone.

Proposed replacements: ubiquitin-like protein binding

Summary: FNIP1 associates with the ubiquitin-like ATG8-family protein GABARAPL1.

Reason: PMID:20562859 has exact target-specific interaction records for FNIP1 and GABARAPL1. The records distinguish tagged cellular co-immunoprecipitation from the GABARAPL1 GST/radiolabeled-FNIP1 pulldown. Both partners are ATG8-family ubiquitin-like conjugating proteins, so GO:0032182 preserves the informative partner class. This does not make FNIP1 a ubiquitin-conjugating enzyme or establish a cargo-adaptor function from association alone.

Proposed replacements: ubiquitin-like protein binding

Summary: FNIP1 associates with the HIV-1 protease construct in the curated interaction assays.

Reason: PMID:22190034 has three exact positive IntAct records linking human FNIP1 to the viral protease Q9Q2G4, including anti-tag co-immunoprecipitation and pulldown records. The curated bait bears a position-25 mutation and the records use spoke-expanded associations. Retain this experimentally reported association as non-core without treating it as FNIP1 proteolysis, a demonstrated native infection complex, or binding to an independently active enzyme. The accessible abstract and target-specific records do not supply a complete target-level primary validation narrative; missing full-text access is not evidence that the association is false.

Summary: FNIP1 participates in an FLCN complex associated with the ubiquitin-like GABARAP protein.

Reason: PMID:25126726 reports GABARAP-associated FNIP1/FLCN and enhanced FLCN–GABARAP co-immunoprecipitation with FNIP1, while FNIP2 has the stronger effect. Preserve both original WITH/FROM partners. The proposed GAP-protein and ubiquitin-like-protein binding terms specify the two established partner classes, not a purified binary FNIP1 interaction with each component or a universal autophagy-adaptor mechanism. Later FNIP1 LIR-mutant evidence corroborates the GABARAP interface.

Proposed replacements: GTPase activating protein binding ubiquitin-like protein binding

Summary: FNIP1 associates with the Hsp90 client glucocorticoid receptor NR3C1 in cellular complexes.

Reason: PMID:27353360 detects glucocorticoid receptor NR3C1 in endogenous FNIP1 immunoprecipitates and corroborates FNIP-associated complexes with tagged proteins in HEK293 cells. Client abundance or activity also changes after FNIP perturbation. These are positive client-network observations, but this experiment does not distinguish a FNIP1-proximal client contact from association through Hsp90 or another complex component. Retain the original association as KEEP_AS_NON_CORE rather than introduce a more specific binding claim from this shared-client context. The separate purified FNIP1–Hsp90 and FNIP1–FLCN reconstitutions do not establish the same contact for every client. This source-specific limit does not make purified binary assays a universal requirement; the independently supported AMPK substrate interaction remains distinct.

Summary: FNIP1 directly binds Hsp90 as a functional co-chaperone.

Reason: PMID:27353360 shows FNIP1–Hsp90 association in cells and direct binding with purified proteins, maps the FNIP1 C-terminal region, and measures inhibition of the Hsp90 ATPase cycle. GO:0051879 Hsp90 protein binding makes this generic partner-specific row informative and complements the independently retained chaperone-binding and ATPase-inhibitor annotations. Full-length protein and 929–1166 experimental fragment assays are not generalized to all natural products.

Proposed replacements: Hsp90 protein binding

Summary: FNIP1 associates with the Hsp90 client CDK4 in cellular complexes.

Reason: PMID:27353360 detects CDK4 in endogenous FNIP1 immunoprecipitates and corroborates FNIP-associated complexes with tagged proteins in HEK293 cells. Client abundance or activity also changes after FNIP perturbation. These are positive client-network observations, but this experiment does not distinguish a FNIP1-proximal client contact from association through Hsp90 or another complex component. Retain the original association as KEEP_AS_NON_CORE rather than introduce a more specific binding claim from this shared-client context. The separate purified FNIP1–Hsp90 and FNIP1–FLCN reconstitutions do not establish the same contact for every client. This source-specific limit does not make purified binary assays a universal requirement; the independently supported AMPK substrate interaction remains distinct.

Summary: FNIP1 associates with the Hsp90 client BRAF in cellular complexes.

Reason: PMID:27353360 detects BRAF in endogenous FNIP1 immunoprecipitates and corroborates FNIP-associated complexes with tagged proteins in HEK293 cells. Client abundance or activity also changes after FNIP perturbation. These are positive client-network observations, but this experiment does not distinguish a FNIP1-proximal client contact from association through Hsp90 or another complex component. Retain the original association as KEEP_AS_NON_CORE rather than introduce a more specific binding claim from this shared-client context. The separate purified FNIP1–Hsp90 and FNIP1–FLCN reconstitutions do not establish the same contact for every client. This source-specific limit does not make purified binary assays a universal requirement; the independently supported AMPK substrate interaction remains distinct.

Summary: FNIP1 associates with the Hsp90 co-chaperone STIP1/HOP.

Reason: PMID:27353360 detects STIP1/HOP in endogenous and tagged FNIP-associated complexes in HEK293 cells. Retain this supported co-chaperone-network association as non-core. The partner is itself a co-chaperone; that label alone does not establish an independently measured protein-folding activity or a specific direct FNIP1 interface. The direct FNIP1–Hsp90 experiment is separate and is not transferred to every co-complex component.

Summary: FNIP1 associates with the Hsp90 co-chaperone PTGES3/p23.

Reason: PMID:27353360 detects PTGES3/p23 in endogenous and tagged FNIP-associated complexes in HEK293 cells. Retain this supported co-chaperone-network association as non-core. The partner is itself a co-chaperone; that label alone does not establish an independently measured protein-folding activity or a specific direct FNIP1 interface. The direct FNIP1–Hsp90 experiment is separate and is not transferred to every co-complex component.

Summary: FNIP1 associates with the Hsp90 co-chaperone CDC37.

Reason: PMID:27353360 detects CDC37 in endogenous and tagged FNIP-associated complexes in HEK293 cells. Retain this supported co-chaperone-network association as non-core. The partner is itself a co-chaperone; that label alone does not establish an independently measured protein-folding activity or a specific direct FNIP1 interface. The direct FNIP1–Hsp90 experiment is separate and is not transferred to every co-complex component.

Summary: FNIP1 binds folliculin and facilitates its loading onto Hsp90.

Reason: PMID:27353360 directly tests bacterially expressed FNIP1–FLCN binding and shows that FNIP1 permits Hsp90–FLCN complex assembly when Hsp90 and FLCN alone do not associate detectably. GO:0032794 identifies the established FLCN GAP-partner class; the measured operation here is co-chaperone client handling, not activation of GAP catalysis. The direct reconstitution supports this interaction without establishing identical behavior for all natural FNIP1 products.

Proposed replacements: GTPase activating protein binding

Summary: FNIP1 contributes LIR-dependent binding of the ubiquitin-like GABARAP protein.

Reason: PMID:34597140 shows human FNIP1-dependent FLCN-complex binding to GABARAP and loss of that interaction after the FNIP1 Y583A/V586A LIR mutation, without loss of FLCN association. GABARAP is an ATG8-family ubiquitin-like conjugating protein, making GO:0032182 more informative than generic protein binding for this exact partner. Preserve the contributes_to qualifier and complex context; the FNIP2 peptide structure and its direct SPR affinity are not attributed to isolated FNIP1.

Proposed replacements: ubiquitin-like protein binding

Summary: The conserved cytoplasmic localization is supported, with cytosolic and lysosomal-membrane pools resolved in human cells.

Reason: The original positive PAINT IBD for cytoplasm at PTN001092003 (Unikonts) lies on the verified human FNIP1 target path, with the exact 1,166-residue target sequence. There is no target-specific loss or divergence, and neither the donor count nor human FNIP1 appearing among the descendant evidence is a defect. PMID:29848618 directly follows endogenous-locus-tagged FNIP1 in human HeLa cells under fed and starved conditions. Cytosol (GO:0005829) and lysosomal membrane (GO:0005765) are separately retained, experimentally supported locations in this review; official part_of/is_a paths place both within cytoplasm. TOO_GENERAL assesses that gene-level term redundancy, not the validity of this source assertion, and does not relabel an older reticular pattern as exclusively lysosomal.

Summary: Tagged human FNIP1 and FLCN colocalize in a reticular cytoplasmic pattern in transfected HeLa cells.

Reason: PMID:17028174 reports the cloned human 1,166-residue FNIP1 sequence and cytoplasmic reticular colocalization of HA-FNIP1 with FLAG-FLCN after transient cotransfection in HeLa cells. This is genuine source-specific localization evidence; the same paragraph assigns additional nuclear localization to FLCN, not FNIP1. The two original UniProt and ComplexPortal records share the exported seed key and remain represented together. Later endogenous-locus tagging independently supports the regulated FNIP1 localization cycle (PMID:29848618). Cytosol (GO:0005829) and lysosomal membrane (GO:0005765) are separately retained, experimentally supported locations in this review; official part_of/is_a paths place both within cytoplasm. TOO_GENERAL assesses that gene-level term redundancy, not the validity of this source assertion, and does not relabel an older reticular pattern as exclusively lysosomal.

Summary: The curated cytoplasmic FNIP1 assertion agrees with independently verified human localization, while the cited paper’s specific assay remains unverified.

Reason: The PMID:18663353 cache is abstract-only and foregrounds FNIP2/FNIPL localization; the inspected abstract does not resolve the exact FNIP1 localization experiment. This does not establish a paralog error: the original experimental assertion and citation are preserved, and independent human FNIP1 data in PMID:17028174 and PMID:29848618 establish the location. The reviewed FNIP1 UniProt record also retains this paper as localization support. Cytosol (GO:0005829) and lysosomal membrane (GO:0005765) are separately retained, experimentally supported locations in this review; official part_of/is_a paths place both within cytoplasm. TOO_GENERAL assesses that gene-level term redundancy, not the validity of this source assertion, and does not relabel an older reticular pattern as exclusively lysosomal.

Summary: Electronic cytoplasmic localization agrees with directly established human FNIP1 localization.

Reason: The original GO_REF:0000120/ARBA and ortholog-supported assertion is biologically consistent with the human FNIP1 experiments in PMID:17028174 and PMID:29848618. This assessment does not claim an independent replay of each individual ARBA or ortholog experiment. Cytosol (GO:0005829) and lysosomal membrane (GO:0005765) are separately retained, experimentally supported locations in this review; official part_of/is_a paths place both within cytoplasm. TOO_GENERAL assesses that gene-level term redundancy, not the validity of this source assertion, and does not relabel an older reticular pattern as exclusively lysosomal.

Summary: FNIP1-GFP localizes to the limiting membrane of lysosomes in live HeLa cells.

Reason: PMID:24081491 reports FNIP1-GFP colocalization with dextran-labeled lysosomes and coexpressed FLCN; vacuolin-enlarged organelles distinguish limiting-membrane association from luminal filling (Figure 3 and selected Methods). The FNIP1 construct is identified as BC001956.1. The retained official GenBank accession encodes a human 508-residue clone differing at one position from current Q8TF40-2, so the Methods label of full-length FNIP1 does not establish the 1,166-residue canonical product or an exact current isoform assignment. The accompanying full-length FLCN construct is explicitly mouse. These are tagged overexpression experiments in human HeLa cells, not endogenous FNIP1 imaging. PMID:29848618 independently establishes regulated localization from the endogenous human FNIP1 locus and explains the more constitutive localization produced by overexpression. No localization is assigned to every natural splice product.

Summary: Endogenous-locus-tagged FNIP1 is recruited to lysosomes during amino-acid starvation in human cells.

Reason: Although the normal PMID:29848618 cache is abstract-only, selected Results, Figure 8 caption and Methods were read in the retained original full-text XML. CRISPR insertion of an N-terminal 2×HA tag into two FNIP1 alleles, with a frameshift in the remaining allele, permits specific detection in HeLa cells. FNIP1 is not strongly lysosome-enriched in fed cells but becomes LAMP1-colocalized during starvation; RagC depletion prevents this enrichment. The experiment supports a regulated membrane-associated signaling pool, not exclusive or constitutive lysosomal localization, and does not resolve all natural products.

Summary: FNIP1 is recruited to the lysosomal membrane as a regulated component of the FLCN complex.

Reason: The original UniProt subcellular-location mapping from SL-0157 is supported by the primary microscopy in PMID:24081491 and PMID:29848618. Tagged FNIP1 is resolved on the limiting membrane of enlarged lysosomes in the former study; endogenous-locus 2×HA-FNIP1 becomes lysosome-enriched during amino-acid starvation in the latter. This is a conditional membrane-associated pool, not constitutive occupancy or a claim that FNIP1 is a transmembrane protein. The localization is central to its FLCN-associated nutrient-signaling role.

Summary: The curated cytosolic FNIP1 pool is retained alongside its directly demonstrated lysosomal-membrane pool.

Reason: The inspected PMID:24081491 FNIP1 panels chiefly establish tagged FNIP1 on lysosomal membranes; the diffuse and endogenous-tagged FLCN experiments must not be relabeled as direct endogenous FNIP1 experiments. The existing curated cytosol assertion is nevertheless consistent with the independently established human FNIP1 localization cycle in PMID:29848618 and the reviewed UniProt record. Retain the cytosolic term as a central pool, while distinguishing that corroboration from what the particular 2013 FNIP1 panels demonstrate.

Summary: Human FNIP1 occupies a cytosolic pool under fed conditions and is recruited to lysosomes during starvation.

Reason: Selected original PMID:29848618 Results and Figure 8 describe endogenous-locus 2×HA-FNIP1 in HeLa cells, with little lysosome enrichment in the fed state and marked LAMP1-colocalized enrichment after starvation. The authors conclude that the FLCN–FNIP1 complex cycles on and off lysosomes; their coimmunoprecipitation detects persistent FLCN association across the tested conditions. Together with the retained reviewed UniProt cytosol assignment, this supports the cytosolic pool. It is not a quantitative biochemical measurement of every soluble fraction, an assertion that all cytoplasmic fluorescence is cytosolic, or evidence for every splice product.

Summary: FNIP1 has a cytosolic pool that participates in its regulated FLCN-associated localization cycle.

Reason: The original SL-0091-to-cytosol mapping agrees with the reviewed FNIP1 UniProt localization statement and the human-cell evidence in PMID:29848618. Endogenous-locus-tagged FNIP1 is predominantly non-lysosome-enriched under fed conditions and is recruited to lysosomes during starvation. Cytosol is therefore a relevant basal pool alongside its membrane-associated pool. This does not imply universal cytosolic residence or identical behavior of all three natural products.

Summary: FNIP1 contributes to the GAP activity of the FLCN–FNIP1 complex, directly tested with Rag GTPases.

Reason: PMID:24081491 establishes FNIP1-dependent recruitment and Rag association, while the additionally inspected PMID:24095279 directly measures GAP activity of affinity- and size-exclusion-purified FLCN–FNIP1 complexes from HEK293T cells. Radiolabeled-nucleotide/TLC assays detect GTP hydrolysis stimulation, with the authors reporting a preference for RagD and lower activity than the FLCN–FNIP2 preparation. The supported replacement is contributes_to GO:0005096 GTPase activator activity: this is a contribution to the complex activity, not an independent FNIP1 GAP or an isolated measurement of FNIP1 activating the FLCN enzyme. The inactive isolated controls in that paper are FLCN and FNIP2; an FNIP1-alone assay is not established by those controls. Preserve the original enables qualifier and all four extension atoms as source provenance. The proposed relation change to contributes_to is stated here and encoded in core_functions.contributes_to_molecular_function because the replacement-term schema has no qualifier slot.

Proposed replacements: GTPase activator activity

Summary: FNIP1 supports B-cell adaptation and survival during nutrient limitation.

Reason: The exact mouse donor evidence in PMID:22608497 tests nutrient withdrawal and metabolic inhibitors in Fnip1-deficient B-cell precursors. Loss sensitizes cells to glucose, glutamine and essential-amino-acid limitation and compromises survival and maturation; IL-7 and nutrient supplementation have condition-dependent effects. Retain the starvation-response transfer as a contextual metabolic role, without inferring that FNIP1 itself transports or senses every nutrient.

Summary: FNIP1 associates with OGT, an enzyme that regulates FNIP1 by O-GlcNAcylation.

Reason: PMID:30699359 identifies OGT in endogenous FNIP1 immunoprecipitates and confirms the association by immunoblotting; the FNIP1 C-terminal D fragment also associates with this regulator (Figure 1A–C). The study couples this association to O-GlcNAcylation of FNIP1, which influences Hsp90 binding and co-chaperone regulation. Retain the supported enzyme-binding context as non-core: FNIP1 is the regulated substrate in this interaction, and the data do not assign the modifying enzyme activity to FNIP1.

Summary: FNIP1 associates with PP5, an enzyme that regulates FNIP1 by dephosphorylation.

Reason: PMID:30699359 identifies PP5 in endogenous FNIP1 immunoprecipitates and confirms the association by immunoblotting; the FNIP1 C-terminal D fragment also associates with this regulator (Figure 1A–C). The study couples this association to dephosphorylation of FNIP1, which influences Hsp90 binding and co-chaperone regulation. Retain the supported enzyme-binding context as non-core: FNIP1 is the regulated substrate in this interaction, and the data do not assign the modifying enzyme activity to FNIP1.

Summary: FNIP1 associates with CK2, an enzyme that regulates FNIP1 by phosphorylation.

Reason: PMID:30699359 identifies CK2 in endogenous FNIP1 immunoprecipitates and confirms the association by immunoblotting; the FNIP1 C-terminal D fragment also associates with this regulator (Figure 1A–C). The study couples this association to phosphorylation of FNIP1, which influences Hsp90 binding and co-chaperone regulation. Retain the supported enzyme-binding context as non-core: FNIP1 is the regulated substrate in this interaction, and the data do not assign the modifying enzyme activity to FNIP1.

Summary: Human FNIP1 deficiency disrupts B-cell development and metabolic regulation.

Reason: PMID:32905580 reports three patients with biallelic FNIP1 defects and loss of protein, markedly reduced peripheral B cells and agammaglobulinemia. Detailed measurements in one patient show reduced immature B cells and altered mitochondrial and PI3K/Akt readouts, without an overt bone-marrow maturation block identical to classic agammaglobulinemia. These human observations support the existing B-cell differentiation role, contextual to FNIP1-dependent metabolic and survival control; they do not establish direct lineage instruction or identical effects of every allele. Selected original Results and captions were inspected; detailed Methods are deferred to an uninspected supplement.

Summary: FNIP1 promotes assembly of an FLCN–GABARAP-associated complex.

Reason: PMID:25126726 identifies FNIP1 and FLCN in GABARAP-associated material and shows enhanced FLCN–GABARAP co-immunoprecipitation when FNIP1 is coexpressed in HEK293 cells; FNIP2 produces a stronger effect in those experiments. Retain the specific assembly context and both original input proteins. The experiment concerns an FLCN–GABARAP complex, not a universal protein-assembly catalyst or a purified stoichiometric bridging mechanism for FNIP1. Later FNIP1 LIR-mutant and complementation results independently support this regulated interaction (PMID:34597140).

Summary: FNIP1 can restrain TOR output in a B-cell metabolic context.

Reason: The exact mouse donor Q68FD7 cites PMID:22608497. Fnip1-null pre-B cells show elevated S6 phosphorylation and fail to suppress this readout after AICAR despite AMPK activation. This supports context-dependent negative TOR regulation through the metabolic checkpoint. It does not conflict with the positive FLCN–Rag–TFEB branch in other conditions, and it does not make FNIP1 an mTOR catalytic inhibitor. Another Fnip1 mouse study reports different mTOR readouts in its models (PMID:22709692), so the negative effect is not generalized to all tissues or conditions.

Summary: FNIP1 links AMPK-associated signaling to context-dependent restraint of TOR output.

Reason: PMID:17028174 establishes FNIP1 association with AMPK and FLCN and phosphorylation responses to AMPK/mTOR perturbation. Those experiments do not isolate a universal FNIP1-mediated inhibitory step in TOR signaling. Independent target-specific mouse experiments in PMID:22608497 support impaired AMPK-dependent suppression of S6 phosphorylation after Fnip1 loss. Retain this broad NAS assertion as a contextual regulatory role, with the original source preserved and the corroborating loss-of-function evidence distinguished from its association and phosphorylation assays.

Summary: The same-source TORC1-specific annotation captures this positive signaling contribution.

Reason: PMID:24081491 shows that FNIP1 supports FLCN lysosomal recruitment, Rag association and TFEB regulation in HeLa cells. The separately retained GO:1904263 annotation from this same paper specifies positive regulation of TORC1 signaling and is an ontology descendant of this broader positive TOR term. Mark the broad duplicate as too general while preserving its original source context; this does not negate FNIP1 participation or imply independent FNIP1 kinase/GAP catalysis.

Summary: FNIP1 reduces Hsp90 ATP hydrolysis as part of its co-chaperone mechanism.

Reason: This IBA is consistent with direct target-specific evidence: PMID:27353360 measures inhibition of Hsp90α ATPase activity by purified full-length FNIP1 and its C-terminal 929–1166 fragment (Figure 4 and ATPase Methods); the fragment also binds Hsp90 directly. This is a core regulatory activity that slows the Hsp90 chaperone cycle, not ATP hydrolysis by FNIP1 itself or universal inhibition of unrelated ATPases. Experimental fragments and phosphomutants do not establish equivalence across all natural FNIP1 products. The original PAINT IBD is placed at PTN001092003, on the path to canonical human FNIP1 PTN002502545 in PTHR21634; the target alignment sequence matches UniProt exactly. Human FNIP1 in the descendant evidence is valid experimental grounding of the ancestral inference, not circular transfer. This target assessment does not assert that every other member of the family retains the same activity.

Summary: FNIP1 reduces Hsp90 ATP hydrolysis as part of its co-chaperone mechanism.

Reason: PMID:27353360 measures inhibition of Hsp90α ATPase activity by purified full-length FNIP1 and its C-terminal 929–1166 fragment (Figure 4 and ATPase Methods); the fragment also binds Hsp90 directly. This is a core regulatory activity that slows the Hsp90 chaperone cycle, not ATP hydrolysis by FNIP1 itself or universal inhibition of unrelated ATPases. Experimental fragments and phosphomutants do not establish equivalence across all natural FNIP1 products.

Summary: FNIP1 reduces Hsp90 ATP hydrolysis as part of its co-chaperone mechanism.

Reason: PMID:30699359 measures Hsp90α ATP turnover with bacterially purified FNIP1 D fragment and defined phosphomimetic mutants; graded inhibition accompanies the FNIP1 phosphorylation series (Figure 3 and ATPase Methods). This is a core regulatory activity that slows the Hsp90 chaperone cycle, not ATP hydrolysis by FNIP1 itself or universal inhibition of unrelated ATPases. Experimental fragments and phosphomutants do not establish equivalence across all natural FNIP1 products.

Summary: FNIP1 directly engages Hsp90 as a functional co-chaperone.

Reason: This IBA agrees with direct evidence on human FNIP1: PMID:27353360 demonstrates binding of bacterially expressed FNIP1 to purified Hsp90α, maps Hsp90 engagement to the C-terminal D region and shows FNIP1-dependent assembly of an Hsp90–FLCN complex (Figures 2–3). The binding accompanies ATPase regulation and client handling, so it represents a core co-chaperone interaction rather than an incidental complex association. The inspected constructs do not establish an isoform-specific function or identical activity for every natural FNIP1 product. The original PAINT IBD is placed at PTN001092003, on the path to canonical human FNIP1 PTN002502545 in PTHR21634; the target alignment sequence matches UniProt exactly. Human FNIP1 in the descendant evidence is valid experimental grounding of the ancestral inference, not circular transfer. This target assessment does not assert that every other member of the family retains the same activity.

Summary: FNIP1 directly engages Hsp90 as a functional co-chaperone.

Reason: PMID:27353360 demonstrates binding of bacterially expressed FNIP1 to purified Hsp90α, maps Hsp90 engagement to the C-terminal D region and shows FNIP1-dependent assembly of an Hsp90–FLCN complex (Figures 2–3). The binding accompanies ATPase regulation and client handling, so it represents a core co-chaperone interaction rather than an incidental complex association. The inspected constructs do not establish an isoform-specific function or identical activity for every natural FNIP1 product.

Summary: FNIP1 directly engages Hsp90 as a functional co-chaperone.

Reason: PMID:30699359 demonstrates FNIP1–Hsp90 association and its graded regulation by phosphorylation of the FNIP1 C-terminal region (Figures 1–3). The binding accompanies ATPase regulation and client handling, so it represents a core co-chaperone interaction rather than an incidental complex association. The inspected constructs do not establish an isoform-specific function or identical activity for every natural FNIP1 product.

Summary: FNIP1 contributes to FLCN-dependent positive TORC1 signaling toward the Rag–TFEB pathway.

Reason: PMID:24081491 shows FNIP1-dependent FLCN lysosomal recruitment and Rag engagement, and nuclear TFEB after FNIP1 depletion in human HeLa cells. FNIP1 therefore does functional complex-organizing work in this positive TORC1 signaling branch. The experiments support pathway participation without directly measuring FNIP1 activation of FLCN catalytic turnover; the separate extended enzyme-activator annotation remains unresolved. Endogenous human-cell evidence is distinguished from the paper’s incompletely resolved tagged-construct accession, and the result is not generalized to uniform activation of all mTORC1 substrates.

Summary: FNIP1 supports the positive FLCN–Rag–mTORC1 branch that restrains TFEB.

Reason: PMID:34597140 uses human FNIP1/2-double-knockout cells complemented with wild-type or LIR-mutant FNIP1. Both restore repression of constitutive TFEB/GPNMB activation, while the LIR mutation selectively disrupts GABARAP-dependent complex sequestration and subsequent TFEB activation. This supports FNIP1 as a functional positive signaling partner under the basal conditions tested. Lysosomal sequestration can inhibit this branch, and effects on TFEB are separated from global S6K/4EBP1 output. FNIP2 peptide structures and purified affinity values are not transferred to FNIP1.

Summary: AMPK-sensitive FNIP1 contributes to the positive TORC1–TFEB signaling branch.

Reason: PMID:37079666 tests FNIP1 knockout and reconstitution with wild-type or five-site nonphosphorylatable FNIP1. AMPK-dependent phosphorylation permits TFEB activation, whereas the resistant FNIP1 mutant preserves the inhibitory restraint on TFEB; RagC nucleotide-state epistasis places the effect in the FLCN–Rag pathway. This supports FNIP1 participation in positive TORC1 signaling toward TFEB, regulated by energy stress. The cellular epistasis does not by itself establish independent FNIP1 GAP catalysis or a direct catalytic-activation mechanism.

Summary: FNIP1 is a supported component of positive TORC1 signaling to TFEB, with source-specific assay limits.

Reason: PMID:39423796 places the FLCN–FNIP–RagC/D branch in STING/GABARAP-dependent control of TFEB and tests downstream RagC bypass. The inspected experiments do not independently resolve an FNIP1-specific perturbation underlying this exact IDA; they should not be described as a purified FNIP1 activity assay. Direct FNIP1 knockout/complementation and phosphomutant experiments in PMID:34597140 and PMID:37079666 establish the same functional pathway participation. Retain the supported core process with the original source unchanged and its specific experimental attribution distinguished from the corroborating target-specific studies.

Summary: FNIP1 restrains lysosomal expansion through its regulated TFEB pathway.

Reason: PMID:37079666 links AMPK-dependent FNIP1 phosphorylation to TFEB nuclear entry, lysosomal gene induction and lysosomal expansion. FNIP1 knockout/reconstitution and the nonphosphorylatable mutant support negative regulation of lysosome organization in the tested human-cell conditions. This is a downstream contextual consequence of FNIP1’s FLCN-associated signaling role, not a direct lysosomal membrane-building or hydrolase activity and not a universal response of all natural products.

Summary: FNIP1 is the FLCN-associated subunit of a FNIP–folliculin RagC/D GAP complex.

Reason: PMID:17028174 establishes reciprocal and endogenous FNIP1–FLCN association in HEK293 cells, together with tagged colocalization and FLCN-binding-region experiments. The official GO:1990877 definition explicitly includes mammalian FLCN paired with either FNIP1 or FNIP2, and later PMID:29848618 independently detects an endogenous-locus-tagged FNIP1–FLCN complex across nutrient conditions. The original 2006 paper establishes membership but predates the RagC/D GAP characterization; it is not cited as a purified Rag GAP assay. This component annotation does not assign FLCN’s catalytic contribution independently to FNIP1 or imply equal catalytic behavior or membership of every natural FNIP1 product.

Summary: FNIP1 regulates pro-B-cell progression and survival in the mouse donor model.

Reason: The exact mouse donor Q68FD7 cites PMID:22709692. Two Fnip1 knockout models accumulate pro-B fractions C/C′, transplantation supports a cell-intrinsic defect, and pre-rearranged receptors only partly restore marrow progression; Bcl2 restores peripheral B cells and implicates precursor survival. These are direct Fnip1 experiments, separate from the paper’s conditional Flcn comparison. Retain the original human ISS as contextual regulation of pro-B-cell differentiation, without assigning antigen-receptor recombination or a direct lineage-specification activity to FNIP1.