{"gene":"IFT57","run_date":"2026-06-10T01:55:22","timeline":{"discoveries":[{"year":2002,"finding":"HIPPI (IFT57) forms a heterodimer with HIP-1 through their pseudo death-effector domains (pDEDs); this heterodimer recruits procaspase-8 into a trimeric complex (HIPPI–HIP-1–procaspase-8) and activates caspase-8, launching apoptosis through the extrinsic cell-death pathway. Formation of this complex is promoted by polyglutamine expansion in huntingtin, which reduces HIP-1 binding to Htt and increases free HIP-1 available to bind HIPPI.","method":"Co-immunoprecipitation, yeast two-hybrid, cell-based apoptosis assays, subcellular localization studies","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP demonstrating trimeric complex, multiple orthogonal methods (Y2H, Co-IP, functional apoptosis readout), widely replicated in subsequent studies","pmids":["11788820"],"is_preprint":false},{"year":2008,"finding":"IFT57 is required for IFT20 association with the IFT particle and for ATP-dependent dissociation of kinesin II from the IFT particle in vertebrate photoreceptors; loss of IFT57 results in short outer segments with reduced opsin but does not abolish IFT altogether, indicating IFT57 is required for efficient rather than essential IFT.","method":"Co-immunoprecipitation from zebrafish whole-animal extracts (ift57 mutants vs. wild-type), phenotypic analysis of ift57 and ift88 zebrafish mutants, immunohistochemistry","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP from mutant vs. wild-type animals combined with defined photoreceptor phenotype; single lab but two orthogonal methods","pmids":["18492793"],"is_preprint":false},{"year":2006,"finding":"HIPPI (IFT57) knockout in mice abolishes motile monocilia at the embryonic node, causing randomization of left-right axis patterning (heart looping and embryo turning defects), and downregulates the Sonic hedgehog (Shh) pathway in the neural tube, resulting in failure to establish ventral neural cell fate.","method":"Hippi knockout mouse generation, immunohistochemistry, in situ hybridization for Shh target genes, scanning electron microscopy of node cilia","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with specific cilia and Shh signaling phenotypes, multiple orthogonal readouts in a defined loss-of-function model","pmids":["17027958"],"is_preprint":false},{"year":2017,"finding":"In Chlamydomonas, IFT57 (IFT-B2 subunit) does not play an essential structural role bridging IFT-B1 and IFT-B2 subcomplexes; instead, IFT57 prevents degradation of the IFT particle (stabilizes assembled complex) and is required for transport of specific motility-related axonemal proteins, with its loss disrupting flagellar waveform and cell swimming.","method":"Analysis of Chlamydomonas ift57-1 mutant: flagellar protein composition by mass spectrometry/immunoblot, IFT motility imaging, flagellar waveform analysis","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean mutant with defined flagellar cargo and IFT particle analysis, single lab, multiple biochemical and cell biological readouts","pmids":["28104816"],"is_preprint":false},{"year":2006,"finding":"The C-terminal pseudo death-effector domain (pDED) of HIPPI directly binds a 60 bp upstream sequence (−151 to −92) of the caspase-1 promoter in vitro and in vivo, increasing caspase-1 transcription; HIPPI also binds promoter sequences of caspase-8 and caspase-10, increasing their expression.","method":"EMSA, fluorescence quenching, chromatin immunoprecipitation (ChIP), luciferase reporter assay in HeLa and Neuro2A cells","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP (in vivo) plus EMSA (in vitro) plus functional luciferase assay; single lab, multiple orthogonal methods","pmids":["17173859"],"is_preprint":false},{"year":2007,"finding":"The C-terminal pDED of HIPPI interacts with a specific motif AAAGACATG (−101 to −93) in the caspase-1 upstream sequence; mutations in this motif reduce HIPPI binding and promoter activity. HIPPI similarly interacts with analogous motifs in caspase-8 and caspase-10 promoters.","method":"EMSA with mutated promoter sequences, luciferase reporter assay with mutant promoters in GFP-Hippi-expressing HeLa cells","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-directed mutagenesis of binding motif combined with reporter assay confirms specificity; single lab","pmids":["17623017"],"is_preprint":false},{"year":2009,"finding":"Nuclear translocation of HIPPI is mediated by HIP-1 (which carries a nuclear localization signal); the HIPPI–HIP-1 heterodimer associates with the transcription complex in the nucleus and regulates caspase-1 expression. The R393 residue of HIPPI's pDED is critical for DNA promoter interaction; R393E mutation reduces caspase-1 promoter binding and expression.","method":"HIP-1 knockdown, HIP-1 nuclear localization signal mutants, deletion mutants, co-immunoprecipitation of nuclear transcription complex, R393E mutagenesis with promoter-binding and reporter assays","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site-directed mutagenesis at active residue combined with KD and NLS mutants; single lab, multiple orthogonal methods","pmids":["19934260"],"is_preprint":false},{"year":2011,"finding":"HIPPI binds to the REST/NRSF promoter and increases its expression in neuronal and non-neuronal cells, consequently repressing REST target genes (BDNF, PENK). This nuclear function requires HIP-1 as a nuclear transporter; in a Huntington disease cell model, mutant huntingtin reduces HIP-1 binding, freeing HIP-1–HIPPI to accumulate in the nucleus and upregulate REST.","method":"ChIP assay (HIPPI occupancy at REST promoter), luciferase reporter assay, HIP-1 NLS mutants, HIP-1 knockdown, RT-PCR for REST target genes, Huntington disease cell model","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus functional reporter assay plus KD model; single lab, multiple methods","pmids":["21832040"],"is_preprint":false},{"year":2003,"finding":"Apoptin interacts with HIPPI both in vitro (GST pulldown/yeast two-hybrid) and in human cells (co-localization in cytoplasm of normal cells); Apoptin binds the C-terminal half of HIPPI including its pDED-like motif, while HIPPI binds within the self-multimerization domain of Apoptin. In cancer cells, Apoptin translocates to the nucleus and shows only modest colocalization with cytoplasmic HIPPI.","method":"Yeast two-hybrid screen, in vitro binding assay, co-localization by fluorescence microscopy, domain mapping","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Y2H plus in vitro binding plus cellular colocalization; single lab, multiple methods but no functional reconstitution","pmids":["12745083"],"is_preprint":false},{"year":2007,"finding":"Rybp (DEDAF) physically interacts with HIPPI and synergizes with HIPPI to enhance caspase-8-mediated apoptosis; Rybp appears essential for HIPPI-mediated apoptosis and may mediate or regulate the HIPPI–caspase-8 interaction. Rybp and HIPPI co-localize in a subset of neurons in the developing mouse brain.","method":"Co-immunoprecipitation, apoptosis assays (cell death quantification with caspase-8 readouts), immunofluorescence co-localization in mouse brain sections","journal":"Apoptosis","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP plus functional apoptosis assay with genetic modulation; single lab, two orthogonal methods","pmids":["17874297"],"is_preprint":false},{"year":2005,"finding":"Exogenous HIPPI expression induces apoptosis involving sequential activation of caspase-1 and caspase-8 (prior to caspase-3), Bid cleavage, and release of cytochrome c and AIF from mitochondria, indicating HIPPI triggers both extrinsic and intrinsic (mitochondrial) apoptosis pathways.","method":"GFP-HIPPI overexpression in HeLa and Neuro2A cells; caspase activity assays, cytochrome c/AIF release by fractionation and immunoblot, nuclear fragmentation quantification","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — overexpression with multiple downstream readouts; single lab, functionally coherent pathway placement","pmids":["16364650"],"is_preprint":false},{"year":2008,"finding":"BLOC1S2 interacts specifically with HIPPI but not HIP-1 (by yeast two-hybrid and Co-IP); BLOC1S2 co-localizes with mitochondria and, together with HIPPI, sensitizes glioblastoma cells to staurosporine- and TRAIL-induced apoptosis by enhancing caspase activation, cytochrome c release, and mitochondrial membrane potential disruption.","method":"Yeast two-hybrid screen, co-immunoprecipitation, subcellular colocalization (immunofluorescence), apoptosis sensitization assays","journal":"Apoptosis","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Y2H confirmed by Co-IP, functional sensitization assay; single lab","pmids":["18188704"],"is_preprint":false},{"year":2006,"finding":"Homer1c binds HIPPI (identified by yeast two-hybrid of mouse brain cDNA library); this interaction is specific (Homer2 does not bind HIPPI). Co-expression of Homer1c with HIPPI in cultured striatal neurons prevents HIPPI-induced apoptosis in a Homer1c–HIPPI binding-dependent manner (deletion of HIPPI binding domain abolishes protection).","method":"Yeast two-hybrid, primary neuron culture apoptosis assays with Homer1c co-expression and deletion mutants","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Y2H plus functional neuronal apoptosis assay with domain deletion mutant; single lab","pmids":["17107665"],"is_preprint":false},{"year":2016,"finding":"A homozygous hypomorphic mutation in IFT57 in humans causes oral-facial-digital syndrome with skeletal dysplasia; patient fibroblasts show significantly decreased anterograde ciliary transport and reduced sonic hedgehog signaling compared to controls, establishing IFT57 as required for ciliary transport and Shh signaling in human cells.","method":"Exome sequencing, homozygosity mapping, splicing assay, ciliary transport assay and Shh signaling measurement in patient-derived fibroblasts","journal":"Clinical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional cellular assays in patient-derived cells showing reduced IFT and Shh signaling; single report but with direct functional readout","pmids":["27060890"],"is_preprint":false},{"year":2025,"finding":"A missense variant p.(Val397Glu) in IFT57 (the predominant expressed variant in a BBS patient) causes primary cilia defects and impairs anterograde IFT; exogenous expression of the variant partially rescued cilia structure, function, and anterograde transport in Ift57-KO mIMCD3 cells but did not rescue primary cilia in retinal IFT57-KO RPE1 cells, indicating a cell-type-specific requirement for IFT57 in ciliogenesis.","method":"Patient fibroblast analysis, IFT57-KO RPE1 and mIMCD3 cell lines, exogenous variant rescue experiments, cilia structure/function and anterograde transport assays","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined KO rescue experiment with variant, multiple cell types, functional IFT assay; single lab","pmids":["40273360"],"is_preprint":false},{"year":2006,"finding":"The pseudo death-effector domain (pDED) of HIPPI was successfully crystallized (space group P4(1), two molecules per asymmetric unit), enabling structural determination of the domain responsible for HIP-1 interaction and caspase-8 recruitment.","method":"Protein expression, purification, and X-ray crystallography (preliminary crystallographic analysis)","journal":"Acta crystallographica Section F","confidence":"Low","confidence_rationale":"Tier 1 / Weak — crystallization reported but no structure-function validation described in the abstract; preliminary report only","pmids":["17142908"],"is_preprint":false},{"year":2007,"finding":"Crystal structure of HIP-1 coiled-coil domain (residues 371–481) at 2.8 Å shows a partially opened coiled coil with a basic surface suitable for HIPPI binding; residues F432 and K474 are important for HIPPI binding. The interaction module is a coiled coil, not a death-effector domain as previously predicted.","method":"X-ray crystallography at 2.8 Å resolution, structural modeling","journal":"Journal of molecular biology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — crystal structure of binding partner (HIP-1) with identification of HIPPI-binding surface; functional mutagenesis of HIPPI binding not done in this paper, single study","pmids":["18155047"],"is_preprint":false}],"current_model":"IFT57 (also known as HIPPI) is a dual-function protein: as an intraflagellar transport (IFT) component it is part of IFT complex B (IFT-B2), where it stabilizes the assembled IFT particle, is required for IFT20 association with the particle, mediates ATP-dependent kinesin-II dissociation from the IFT particle, and transports specific motility-related cargoes—with loss causing cilia assembly defects, reduced Sonic hedgehog signaling, and left-right axis patterning defects; as a pro-apoptotic signaling protein (HIPPI), its C-terminal pseudo death-effector domain heterodimerizes with HIP-1, and when freed from huntingtin-bound HIP-1 (as in Huntington disease), this heterodimer recruits procaspase-8 to initiate extrinsic apoptosis, while nuclear-translocated HIPPI–HIP-1 also directly binds promoter sequences of caspase-1, caspase-8, caspase-10, and REST to upregulate their transcription."},"narrative":{"mechanistic_narrative":"IFT57 is a dual-function protein that operates both as a structural component of the intraflagellar transport (IFT) machinery and as a pro-apoptotic signaling adaptor (HIPPI) [PMID:11788820, PMID:17027958]. As an IFT-B2 subunit, IFT57 is required for IFT20 association with the IFT particle and for ATP-dependent dissociation of kinesin-II from the particle, and it stabilizes the assembled IFT complex against degradation while supporting transport of specific motility-related axonemal cargoes rather than serving as an essential structural bridge between IFT-B subcomplexes [PMID:18492793, PMID:28104816]. Loss of IFT57 produces cilia assembly and motility defects: knockout mice lack motile node monocilia, randomize left-right axis patterning, and show downregulated Sonic hedgehog signaling with failure of ventral neural cell-fate specification [PMID:17027958]. In humans, hypomorphic IFT57 mutations reduce anterograde ciliary transport and Shh signaling and cause oral-facial-digital syndrome with skeletal dysplasia, and a missense variant impairing anterograde IFT is associated with Bardet-Biedl-spectrum ciliopathy in a cell-type-specific manner [PMID:27060890, PMID:40273360]. In its second role, IFT57/HIPPI heterodimerizes with HIP-1 through their pseudo death-effector domains and recruits procaspase-8 into a trimeric complex that activates the extrinsic apoptosis pathway, a complex favored when polyglutamine-expanded huntingtin frees HIP-1 from huntingtin [PMID:11788820]. Beyond caspase recruitment, the HIPPI pDED directly binds promoter elements of caspase-1, caspase-8, and caspase-10 and of REST/NRSF to drive their transcription, with HIP-1 supplying the nuclear localization required for this transcriptional function [PMID:17173859, PMID:19934260, PMID:21832040].","teleology":[{"year":2002,"claim":"Established IFT57/HIPPI as a pro-apoptotic adaptor by showing how it links the Huntington disease protein HIP-1 to caspase activation.","evidence":"Co-IP, yeast two-hybrid, and cell-based apoptosis assays defining a HIPPI-HIP-1-procaspase-8 trimeric complex","pmids":["11788820"],"confidence":"High","gaps":["Does not address IFT57's ciliary function","Physiological relevance of the apoptotic complex in vivo not established"]},{"year":2003,"claim":"Identified additional cytoplasmic binding partners of HIPPI, broadening its potential interaction network.","evidence":"Yeast two-hybrid, in vitro binding, and colocalization mapping Apoptin to the C-terminal/pDED region of HIPPI","pmids":["12745083"],"confidence":"Medium","gaps":["No functional reconstitution of the Apoptin-HIPPI interaction","Significance for apoptosis or ciliary function unresolved"]},{"year":2005,"claim":"Placed HIPPI-induced cell death in a defined caspase cascade engaging both extrinsic and intrinsic pathways.","evidence":"GFP-HIPPI overexpression with caspase activity, Bid cleavage, and mitochondrial cytochrome c/AIF release readouts","pmids":["16364650"],"confidence":"Medium","gaps":["Based on overexpression rather than endogenous protein","Causal ordering of caspase-1 vs caspase-8 activation not fully resolved"]},{"year":2006,"claim":"Revealed a transcriptional arm of HIPPI function by showing its pDED directly binds caspase promoter DNA to upregulate caspase expression.","evidence":"EMSA, fluorescence quenching, ChIP, and luciferase reporter assays mapping HIPPI binding to a caspase-1 upstream sequence","pmids":["17173859"],"confidence":"Medium","gaps":["Single lab; in vivo physiological role of promoter binding not established","How a cytoplasmic adaptor accesses chromatin unaddressed in this study"]},{"year":2006,"claim":"Defined an essential ciliary developmental role by demonstrating that HIPPI/IFT57 loss disrupts node cilia, left-right patterning, and Shh signaling.","evidence":"Hippi knockout mouse with SEM of node cilia, in situ hybridization of Shh targets, and immunohistochemistry","pmids":["17027958"],"confidence":"High","gaps":["Mechanistic link between IFT57 and Shh transduction not dissected here","Relationship between ciliary and apoptotic functions unresolved"]},{"year":2006,"claim":"Identified Homer1c as a partner that antagonizes HIPPI-induced neuronal apoptosis.","evidence":"Yeast two-hybrid and primary striatal neuron apoptosis assays with HIPPI-binding-domain deletion mutants","pmids":["17107665"],"confidence":"Medium","gaps":["Mechanism of protection not defined","Endogenous relevance in disease context untested"]},{"year":2007,"claim":"Pinpointed the specific promoter motif recognized by the HIPPI pDED, establishing sequence-specific DNA binding.","evidence":"EMSA with mutated promoter sequences and luciferase reporter assays in GFP-Hippi HeLa cells","pmids":["17623017"],"confidence":"Medium","gaps":["Single lab","Structural basis of motif recognition not determined"]},{"year":2007,"claim":"Identified Rybp/DEDAF as a cofactor required for HIPPI-mediated caspase-8 apoptosis.","evidence":"Co-IP, caspase-8 apoptosis assays with genetic modulation, and neuronal colocalization","pmids":["17874297"],"confidence":"Medium","gaps":["Whether Rybp directly bridges HIPPI to caspase-8 not resolved","Single lab"]},{"year":2008,"claim":"Defined IFT57's biochemical role within the IFT particle as required for IFT20 incorporation and kinesin-II release.","evidence":"Reciprocal Co-IP from zebrafish ift57 mutant vs wild-type extracts plus photoreceptor phenotyping","pmids":["18492793"],"confidence":"High","gaps":["Mechanism of ATP-dependent kinesin dissociation not biochemically reconstituted","IFT remains partially functional, leaving IFT57's precise contribution graded"]},{"year":2008,"claim":"Identified BLOC1S2 as a HIPPI-specific (not HIP-1-binding) partner that promotes mitochondrial apoptotic sensitization.","evidence":"Yeast two-hybrid, Co-IP, colocalization, and apoptosis sensitization assays in glioblastoma cells","pmids":["18188704"],"confidence":"Medium","gaps":["Direct vs indirect link to mitochondrial apoptosis machinery unclear","Single lab"]},{"year":2009,"claim":"Resolved how the cytoplasmic HIPPI reaches the nucleus and identified the catalytic-like residue for promoter binding.","evidence":"HIP-1 knockdown, NLS mutants, nuclear Co-IP, and R393E mutagenesis with reporter assays","pmids":["19934260"],"confidence":"Medium","gaps":["Composition of the nuclear transcription complex incompletely defined","Single lab"]},{"year":2011,"claim":"Extended HIPPI's transcriptional targets to REST/NRSF, linking nuclear HIPPI to neuronal gene repression relevant to Huntington disease.","evidence":"ChIP, luciferase reporter, HIP-1 NLS/knockdown manipulation, and RT-PCR of REST targets in a HD cell model","pmids":["21832040"],"confidence":"Medium","gaps":["In vivo relevance to HD neurodegeneration not established","Single lab"]},{"year":2016,"claim":"Established IFT57 as a human ciliopathy gene by linking a hypomorphic mutation to reduced IFT and Shh signaling.","evidence":"Exome sequencing, homozygosity mapping, and ciliary transport/Shh assays in patient fibroblasts","pmids":["27060890"],"confidence":"Medium","gaps":["Single family report","Genotype-phenotype mechanism in skeletal tissue not detailed"]},{"year":2017,"claim":"Clarified that IFT57 is not an essential structural bridge but instead stabilizes the IFT particle and transports specific motility cargoes.","evidence":"Chlamydomonas ift57-1 mutant flagellar proteomics, IFT motility imaging, and waveform analysis","pmids":["28104816"],"confidence":"Medium","gaps":["Molecular basis of cargo selectivity unknown","Single lab; conservation of role across species inferred"]},{"year":2025,"claim":"Demonstrated cell-type-specific requirement for IFT57 in ciliogenesis through variant rescue in distinct knockout cell lines.","evidence":"IFT57-KO RPE1 and mIMCD3 cells with exogenous p.(Val397Glu) variant rescue and anterograde IFT assays","pmids":["40273360"],"confidence":"Medium","gaps":["Mechanism of cell-type-specific dependence unresolved","Single lab"]},{"year":null,"claim":"How IFT57's ciliary transport role and its HIP-1-dependent apoptotic/transcriptional role are coordinated within a single cell, and whether they share regulatory inputs, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No study integrates the ciliary and apoptotic functions mechanistically","No high-resolution structure of the IFT57 pDED-HIP-1 complex with functional validation","Endogenous physiological balance between the two roles undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[4,5,6]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[4,7]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[2,3,14]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[6,7]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[8]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,10]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,13]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,13]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[1,3]}],"complexes":["IFT complex B (IFT-B2)","HIPPI-HIP-1-procaspase-8 complex"],"partners":["HIP-1","IFT20","PROCASPASE-8","RYBP","BLOC1S2","HOMER1","APOPTIN"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NWB7","full_name":"Intraflagellar transport protein 57 homolog","aliases":["Dermal papilla-derived protein 8","Estrogen-related receptor beta-like protein 1","HIP1-interacting protein","MHS4R2"],"length_aa":429,"mass_kda":49.1,"function":"Required for the formation of cilia. Plays an indirect role in sonic hedgehog signaling, cilia being required for all activity of the hedgehog pathway (By similarity). Together with RAB23 and KIF17, it is required for the localization of specific G protein-coupled receptors, such as dopamime receptor DRD1, to primary cilia (PubMed:26182404). Has pro-apoptotic function via its interaction with HIP1, leading to recruit caspase-8 (CASP8) and trigger apoptosis. Has the ability to bind DNA sequence motif 5'-AAAGACATG-3' present in the promoter of caspase genes such as CASP1, CASP8 and CASP10, suggesting that it may act as a transcription regulator; however the relevance of such function remains unclear","subcellular_location":"Cell projection, cilium; Cytoplasm, cytoskeleton, cilium basal body","url":"https://www.uniprot.org/uniprotkb/Q9NWB7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IFT57","classification":"Not Classified","n_dependent_lines":20,"n_total_lines":1208,"dependency_fraction":0.016556291390728478},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"HSPB11","stoichiometry":4.0},{"gene":"PRPF19","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/IFT57","total_profiled":1310},"omim":[{"mim_id":"619516","title":"BIFUNCTIONAL APOPTOSIS REGULATOR; BFAR","url":"https://www.omim.org/entry/619516"},{"mim_id":"617927","title":"OROFACIODIGITAL SYNDROME XVIII; OFD18","url":"https://www.omim.org/entry/617927"},{"mim_id":"617094","title":"INTRAFLAGELLAR TRANSPORT 52; IFT52","url":"https://www.omim.org/entry/617094"},{"mim_id":"617083","title":"DYNEIN, CYTOPLASMIC 2, LIGHT INTERMEDIATE CHAIN 1; DYNC2LI1","url":"https://www.omim.org/entry/617083"},{"mim_id":"614394","title":"INTRAFLAGELLAR TRANSPORT 20; IFT20","url":"https://www.omim.org/entry/614394"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Golgi apparatus","reliability":"Approved"},{"location":"Primary cilium","reliability":"Approved"},{"location":"Basal body","reliability":"Approved"},{"location":"Mid piece","reliability":"Approved"},{"location":"Primary cilium transition zone","reliability":"Additional"},{"location":"Centriolar satellite","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/IFT57"},"hgnc":{"alias_symbol":["FLJ10147","HIPPI","MHS4R2"],"prev_symbol":["ESRRBL1"]},"alphafold":{"accession":"Q9NWB7","domains":[{"cath_id":"1.10.418","chopping":"38-160","consensus_level":"high","plddt":84.5538,"start":38,"end":160},{"cath_id":"1.20.5","chopping":"260-367","consensus_level":"medium","plddt":93.9169,"start":260,"end":367}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NWB7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NWB7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NWB7-F1-predicted_aligned_error_v6.png","plddt_mean":76.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IFT57","jax_strain_url":"https://www.jax.org/strain/search?query=IFT57"},"sequence":{"accession":"Q9NWB7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NWB7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NWB7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NWB7"}},"corpus_meta":[{"pmid":"11788820","id":"PMC_11788820","title":"Recruitment and activation of caspase-8 by the Huntingtin-interacting protein Hip-1 and a novel partner Hippi.","date":"2002","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/11788820","citation_count":232,"is_preprint":false},{"pmid":"18492793","id":"PMC_18492793","title":"The intraflagellar transport protein IFT57 is required for cilia maintenance and regulates IFT-particle-kinesin-II dissociation in vertebrate photoreceptors.","date":"2008","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/18492793","citation_count":109,"is_preprint":false},{"pmid":"19136023","id":"PMC_19136023","title":"Early defects in photoreceptor outer segment morphogenesis in zebrafish ift57, ift88 and ift172 Intraflagellar Transport mutants.","date":"2009","source":"Vision research","url":"https://pubmed.ncbi.nlm.nih.gov/19136023","citation_count":80,"is_preprint":false},{"pmid":"17027958","id":"PMC_17027958","title":"Hippi is essential for node cilia assembly and Sonic hedgehog signaling.","date":"2006","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/17027958","citation_count":78,"is_preprint":false},{"pmid":"19517571","id":"PMC_19517571","title":"Zebrafish ift57, ift88, and ift172 intraflagellar transport mutants disrupt cilia but do not affect hedgehog signaling.","date":"2009","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/19517571","citation_count":60,"is_preprint":false},{"pmid":"18637945","id":"PMC_18637945","title":"Huntington's disease: roles of huntingtin-interacting protein 1 (HIP-1) and its molecular partner HIPPI in the regulation of apoptosis and transcription.","date":"2008","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/18637945","citation_count":35,"is_preprint":false},{"pmid":"12745083","id":"PMC_12745083","title":"The viral death protein Apoptin interacts with Hippi, the protein interactor of Huntingtin-interacting protein 1.","date":"2003","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/12745083","citation_count":32,"is_preprint":false},{"pmid":"16364650","id":"PMC_16364650","title":"Induction of apoptosis in cells expressing exogenous Hippi, a molecular partner of huntingtin-interacting protein Hip1.","date":"2005","source":"Neurobiology of disease","url":"https://pubmed.ncbi.nlm.nih.gov/16364650","citation_count":24,"is_preprint":false},{"pmid":"17874297","id":"PMC_17874297","title":"Rybp interacts with Hippi and enhances Hippi-mediated apoptosis.","date":"2007","source":"Apoptosis : an international journal on programmed cell death","url":"https://pubmed.ncbi.nlm.nih.gov/17874297","citation_count":23,"is_preprint":false},{"pmid":"21832040","id":"PMC_21832040","title":"Regulation of RE1 protein silencing transcription factor (REST) expression by HIP1 protein interactor (HIPPI).","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21832040","citation_count":19,"is_preprint":false},{"pmid":"27060890","id":"PMC_27060890","title":"Autosomal recessive IFT57 hypomorphic mutation cause ciliary transport defect in unclassified oral-facial-digital syndrome with short stature and brachymesophalangia.","date":"2016","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27060890","citation_count":19,"is_preprint":false},{"pmid":"18188704","id":"PMC_18188704","title":"BLOC1S2 interacts with the HIPPI protein and sensitizes NCH89 glioblastoma cells to apoptosis.","date":"2008","source":"Apoptosis : an international journal on programmed cell death","url":"https://pubmed.ncbi.nlm.nih.gov/18188704","citation_count":17,"is_preprint":false},{"pmid":"18155047","id":"PMC_18155047","title":"Crystal structure at 2.8 A of Huntingtin-interacting protein 1 (HIP1) coiled-coil domain reveals a charged surface suitable for HIP1 protein interactor (HIPPI).","date":"2007","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18155047","citation_count":15,"is_preprint":false},{"pmid":"28474836","id":"PMC_28474836","title":"The Ciliary Protein IFT57 in the Macronucleus of Paramecium.","date":"2017","source":"The Journal of eukaryotic microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/28474836","citation_count":13,"is_preprint":false},{"pmid":"28185571","id":"PMC_28185571","title":"HIPPI: highly accurate protein family classification with ensembles of HMMs.","date":"2016","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/28185571","citation_count":13,"is_preprint":false},{"pmid":"19934260","id":"PMC_19934260","title":"Transcription regulation of caspase-1 by R393 of HIPPI and its molecular partner HIP-1.","date":"2009","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/19934260","citation_count":11,"is_preprint":false},{"pmid":"11832235","id":"PMC_11832235","title":"Hip1 and Hippi participate in a novel cell death-signaling pathway.","date":"2002","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/11832235","citation_count":11,"is_preprint":false},{"pmid":"28104816","id":"PMC_28104816","title":"IFT57 stabilizes the assembled intraflagellar transport complex and mediates transport of motility-related flagellar cargo.","date":"2017","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/28104816","citation_count":10,"is_preprint":false},{"pmid":"17623017","id":"PMC_17623017","title":"Interactions of HIPPI, a molecular partner of Huntingtin interacting protein HIP1, with the specific motif present at the putative promoter sequence of the caspase-1, caspase-8 and caspase-10 genes.","date":"2007","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/17623017","citation_count":10,"is_preprint":false},{"pmid":"17173859","id":"PMC_17173859","title":"Interaction of HIPPI with putative promoter sequence of caspase-1 in vitro and in vivo.","date":"2006","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/17173859","citation_count":10,"is_preprint":false},{"pmid":"17107665","id":"PMC_17107665","title":"Homer1c interacts with Hippi and protects striatal neurons from apoptosis.","date":"2006","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/17107665","citation_count":8,"is_preprint":false},{"pmid":"34079292","id":"PMC_34079292","title":"Silencing HIPPI Suppresses Tumor Progression in Non-Small-Cell Lung Cancer by Inhibiting DNA Replication.","date":"2021","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/34079292","citation_count":6,"is_preprint":false},{"pmid":"40273360","id":"PMC_40273360","title":"Defective IFT57 underlies a novel cause of Bardet-Biedl syndrome.","date":"2025","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/40273360","citation_count":2,"is_preprint":false},{"pmid":"39201643","id":"PMC_39201643","title":"CD47 and IFT57 Are Colinear Genes That Are Highly Coexpressed in Most Cancers and Exhibit Parallel Cancer-Specific Correlations with Survival.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39201643","citation_count":2,"is_preprint":false},{"pmid":"17142908","id":"PMC_17142908","title":"Cloning, expression, purification, crystallization and preliminary crystallographic analysis of pseudo death-effector domain of HIPPI, a molecular partner of Huntingtin-interacting protein HIP-1.","date":"2006","source":"Acta crystallographica. Section F, Structural biology and crystallization communications","url":"https://pubmed.ncbi.nlm.nih.gov/17142908","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12347,"output_tokens":4491,"usd":0.052203,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12519,"output_tokens":4389,"usd":0.08616,"stage2_stop_reason":"end_turn"},"total_usd":0.138363,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"HIPPI (IFT57) forms a heterodimer with HIP-1 through their pseudo death-effector domains (pDEDs); this heterodimer recruits procaspase-8 into a trimeric complex (HIPPI–HIP-1–procaspase-8) and activates caspase-8, launching apoptosis through the extrinsic cell-death pathway. Formation of this complex is promoted by polyglutamine expansion in huntingtin, which reduces HIP-1 binding to Htt and increases free HIP-1 available to bind HIPPI.\",\n      \"method\": \"Co-immunoprecipitation, yeast two-hybrid, cell-based apoptosis assays, subcellular localization studies\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP demonstrating trimeric complex, multiple orthogonal methods (Y2H, Co-IP, functional apoptosis readout), widely replicated in subsequent studies\",\n      \"pmids\": [\"11788820\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"IFT57 is required for IFT20 association with the IFT particle and for ATP-dependent dissociation of kinesin II from the IFT particle in vertebrate photoreceptors; loss of IFT57 results in short outer segments with reduced opsin but does not abolish IFT altogether, indicating IFT57 is required for efficient rather than essential IFT.\",\n      \"method\": \"Co-immunoprecipitation from zebrafish whole-animal extracts (ift57 mutants vs. wild-type), phenotypic analysis of ift57 and ift88 zebrafish mutants, immunohistochemistry\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP from mutant vs. wild-type animals combined with defined photoreceptor phenotype; single lab but two orthogonal methods\",\n      \"pmids\": [\"18492793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"HIPPI (IFT57) knockout in mice abolishes motile monocilia at the embryonic node, causing randomization of left-right axis patterning (heart looping and embryo turning defects), and downregulates the Sonic hedgehog (Shh) pathway in the neural tube, resulting in failure to establish ventral neural cell fate.\",\n      \"method\": \"Hippi knockout mouse generation, immunohistochemistry, in situ hybridization for Shh target genes, scanning electron microscopy of node cilia\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with specific cilia and Shh signaling phenotypes, multiple orthogonal readouts in a defined loss-of-function model\",\n      \"pmids\": [\"17027958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In Chlamydomonas, IFT57 (IFT-B2 subunit) does not play an essential structural role bridging IFT-B1 and IFT-B2 subcomplexes; instead, IFT57 prevents degradation of the IFT particle (stabilizes assembled complex) and is required for transport of specific motility-related axonemal proteins, with its loss disrupting flagellar waveform and cell swimming.\",\n      \"method\": \"Analysis of Chlamydomonas ift57-1 mutant: flagellar protein composition by mass spectrometry/immunoblot, IFT motility imaging, flagellar waveform analysis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean mutant with defined flagellar cargo and IFT particle analysis, single lab, multiple biochemical and cell biological readouts\",\n      \"pmids\": [\"28104816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The C-terminal pseudo death-effector domain (pDED) of HIPPI directly binds a 60 bp upstream sequence (−151 to −92) of the caspase-1 promoter in vitro and in vivo, increasing caspase-1 transcription; HIPPI also binds promoter sequences of caspase-8 and caspase-10, increasing their expression.\",\n      \"method\": \"EMSA, fluorescence quenching, chromatin immunoprecipitation (ChIP), luciferase reporter assay in HeLa and Neuro2A cells\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP (in vivo) plus EMSA (in vitro) plus functional luciferase assay; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"17173859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The C-terminal pDED of HIPPI interacts with a specific motif AAAGACATG (−101 to −93) in the caspase-1 upstream sequence; mutations in this motif reduce HIPPI binding and promoter activity. HIPPI similarly interacts with analogous motifs in caspase-8 and caspase-10 promoters.\",\n      \"method\": \"EMSA with mutated promoter sequences, luciferase reporter assay with mutant promoters in GFP-Hippi-expressing HeLa cells\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-directed mutagenesis of binding motif combined with reporter assay confirms specificity; single lab\",\n      \"pmids\": [\"17623017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Nuclear translocation of HIPPI is mediated by HIP-1 (which carries a nuclear localization signal); the HIPPI–HIP-1 heterodimer associates with the transcription complex in the nucleus and regulates caspase-1 expression. The R393 residue of HIPPI's pDED is critical for DNA promoter interaction; R393E mutation reduces caspase-1 promoter binding and expression.\",\n      \"method\": \"HIP-1 knockdown, HIP-1 nuclear localization signal mutants, deletion mutants, co-immunoprecipitation of nuclear transcription complex, R393E mutagenesis with promoter-binding and reporter assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site-directed mutagenesis at active residue combined with KD and NLS mutants; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"19934260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"HIPPI binds to the REST/NRSF promoter and increases its expression in neuronal and non-neuronal cells, consequently repressing REST target genes (BDNF, PENK). This nuclear function requires HIP-1 as a nuclear transporter; in a Huntington disease cell model, mutant huntingtin reduces HIP-1 binding, freeing HIP-1–HIPPI to accumulate in the nucleus and upregulate REST.\",\n      \"method\": \"ChIP assay (HIPPI occupancy at REST promoter), luciferase reporter assay, HIP-1 NLS mutants, HIP-1 knockdown, RT-PCR for REST target genes, Huntington disease cell model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus functional reporter assay plus KD model; single lab, multiple methods\",\n      \"pmids\": [\"21832040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Apoptin interacts with HIPPI both in vitro (GST pulldown/yeast two-hybrid) and in human cells (co-localization in cytoplasm of normal cells); Apoptin binds the C-terminal half of HIPPI including its pDED-like motif, while HIPPI binds within the self-multimerization domain of Apoptin. In cancer cells, Apoptin translocates to the nucleus and shows only modest colocalization with cytoplasmic HIPPI.\",\n      \"method\": \"Yeast two-hybrid screen, in vitro binding assay, co-localization by fluorescence microscopy, domain mapping\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Y2H plus in vitro binding plus cellular colocalization; single lab, multiple methods but no functional reconstitution\",\n      \"pmids\": [\"12745083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Rybp (DEDAF) physically interacts with HIPPI and synergizes with HIPPI to enhance caspase-8-mediated apoptosis; Rybp appears essential for HIPPI-mediated apoptosis and may mediate or regulate the HIPPI–caspase-8 interaction. Rybp and HIPPI co-localize in a subset of neurons in the developing mouse brain.\",\n      \"method\": \"Co-immunoprecipitation, apoptosis assays (cell death quantification with caspase-8 readouts), immunofluorescence co-localization in mouse brain sections\",\n      \"journal\": \"Apoptosis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP plus functional apoptosis assay with genetic modulation; single lab, two orthogonal methods\",\n      \"pmids\": [\"17874297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Exogenous HIPPI expression induces apoptosis involving sequential activation of caspase-1 and caspase-8 (prior to caspase-3), Bid cleavage, and release of cytochrome c and AIF from mitochondria, indicating HIPPI triggers both extrinsic and intrinsic (mitochondrial) apoptosis pathways.\",\n      \"method\": \"GFP-HIPPI overexpression in HeLa and Neuro2A cells; caspase activity assays, cytochrome c/AIF release by fractionation and immunoblot, nuclear fragmentation quantification\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — overexpression with multiple downstream readouts; single lab, functionally coherent pathway placement\",\n      \"pmids\": [\"16364650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"BLOC1S2 interacts specifically with HIPPI but not HIP-1 (by yeast two-hybrid and Co-IP); BLOC1S2 co-localizes with mitochondria and, together with HIPPI, sensitizes glioblastoma cells to staurosporine- and TRAIL-induced apoptosis by enhancing caspase activation, cytochrome c release, and mitochondrial membrane potential disruption.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, subcellular colocalization (immunofluorescence), apoptosis sensitization assays\",\n      \"journal\": \"Apoptosis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Y2H confirmed by Co-IP, functional sensitization assay; single lab\",\n      \"pmids\": [\"18188704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Homer1c binds HIPPI (identified by yeast two-hybrid of mouse brain cDNA library); this interaction is specific (Homer2 does not bind HIPPI). Co-expression of Homer1c with HIPPI in cultured striatal neurons prevents HIPPI-induced apoptosis in a Homer1c–HIPPI binding-dependent manner (deletion of HIPPI binding domain abolishes protection).\",\n      \"method\": \"Yeast two-hybrid, primary neuron culture apoptosis assays with Homer1c co-expression and deletion mutants\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Y2H plus functional neuronal apoptosis assay with domain deletion mutant; single lab\",\n      \"pmids\": [\"17107665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A homozygous hypomorphic mutation in IFT57 in humans causes oral-facial-digital syndrome with skeletal dysplasia; patient fibroblasts show significantly decreased anterograde ciliary transport and reduced sonic hedgehog signaling compared to controls, establishing IFT57 as required for ciliary transport and Shh signaling in human cells.\",\n      \"method\": \"Exome sequencing, homozygosity mapping, splicing assay, ciliary transport assay and Shh signaling measurement in patient-derived fibroblasts\",\n      \"journal\": \"Clinical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional cellular assays in patient-derived cells showing reduced IFT and Shh signaling; single report but with direct functional readout\",\n      \"pmids\": [\"27060890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A missense variant p.(Val397Glu) in IFT57 (the predominant expressed variant in a BBS patient) causes primary cilia defects and impairs anterograde IFT; exogenous expression of the variant partially rescued cilia structure, function, and anterograde transport in Ift57-KO mIMCD3 cells but did not rescue primary cilia in retinal IFT57-KO RPE1 cells, indicating a cell-type-specific requirement for IFT57 in ciliogenesis.\",\n      \"method\": \"Patient fibroblast analysis, IFT57-KO RPE1 and mIMCD3 cell lines, exogenous variant rescue experiments, cilia structure/function and anterograde transport assays\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined KO rescue experiment with variant, multiple cell types, functional IFT assay; single lab\",\n      \"pmids\": [\"40273360\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The pseudo death-effector domain (pDED) of HIPPI was successfully crystallized (space group P4(1), two molecules per asymmetric unit), enabling structural determination of the domain responsible for HIP-1 interaction and caspase-8 recruitment.\",\n      \"method\": \"Protein expression, purification, and X-ray crystallography (preliminary crystallographic analysis)\",\n      \"journal\": \"Acta crystallographica Section F\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 1 / Weak — crystallization reported but no structure-function validation described in the abstract; preliminary report only\",\n      \"pmids\": [\"17142908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Crystal structure of HIP-1 coiled-coil domain (residues 371–481) at 2.8 Å shows a partially opened coiled coil with a basic surface suitable for HIPPI binding; residues F432 and K474 are important for HIPPI binding. The interaction module is a coiled coil, not a death-effector domain as previously predicted.\",\n      \"method\": \"X-ray crystallography at 2.8 Å resolution, structural modeling\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — crystal structure of binding partner (HIP-1) with identification of HIPPI-binding surface; functional mutagenesis of HIPPI binding not done in this paper, single study\",\n      \"pmids\": [\"18155047\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IFT57 (also known as HIPPI) is a dual-function protein: as an intraflagellar transport (IFT) component it is part of IFT complex B (IFT-B2), where it stabilizes the assembled IFT particle, is required for IFT20 association with the particle, mediates ATP-dependent kinesin-II dissociation from the IFT particle, and transports specific motility-related cargoes—with loss causing cilia assembly defects, reduced Sonic hedgehog signaling, and left-right axis patterning defects; as a pro-apoptotic signaling protein (HIPPI), its C-terminal pseudo death-effector domain heterodimerizes with HIP-1, and when freed from huntingtin-bound HIP-1 (as in Huntington disease), this heterodimer recruits procaspase-8 to initiate extrinsic apoptosis, while nuclear-translocated HIPPI–HIP-1 also directly binds promoter sequences of caspase-1, caspase-8, caspase-10, and REST to upregulate their transcription.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IFT57 is a dual-function protein that operates both as a structural component of the intraflagellar transport (IFT) machinery and as a pro-apoptotic signaling adaptor (HIPPI) [#0, #2]. As an IFT-B2 subunit, IFT57 is required for IFT20 association with the IFT particle and for ATP-dependent dissociation of kinesin-II from the particle, and it stabilizes the assembled IFT complex against degradation while supporting transport of specific motility-related axonemal cargoes rather than serving as an essential structural bridge between IFT-B subcomplexes [#1, #3]. Loss of IFT57 produces cilia assembly and motility defects: knockout mice lack motile node monocilia, randomize left-right axis patterning, and show downregulated Sonic hedgehog signaling with failure of ventral neural cell-fate specification [#2]. In humans, hypomorphic IFT57 mutations reduce anterograde ciliary transport and Shh signaling and cause oral-facial-digital syndrome with skeletal dysplasia, and a missense variant impairing anterograde IFT is associated with Bardet-Biedl-spectrum ciliopathy in a cell-type-specific manner [#13, #14]. In its second role, IFT57/HIPPI heterodimerizes with HIP-1 through their pseudo death-effector domains and recruits procaspase-8 into a trimeric complex that activates the extrinsic apoptosis pathway, a complex favored when polyglutamine-expanded huntingtin frees HIP-1 from huntingtin [#0]. Beyond caspase recruitment, the HIPPI pDED directly binds promoter elements of caspase-1, caspase-8, and caspase-10 and of REST/NRSF to drive their transcription, with HIP-1 supplying the nuclear localization required for this transcriptional function [#4, #6, #7].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established IFT57/HIPPI as a pro-apoptotic adaptor by showing how it links the Huntington disease protein HIP-1 to caspase activation.\",\n      \"evidence\": \"Co-IP, yeast two-hybrid, and cell-based apoptosis assays defining a HIPPI-HIP-1-procaspase-8 trimeric complex\",\n      \"pmids\": [\"11788820\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address IFT57's ciliary function\", \"Physiological relevance of the apoptotic complex in vivo not established\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identified additional cytoplasmic binding partners of HIPPI, broadening its potential interaction network.\",\n      \"evidence\": \"Yeast two-hybrid, in vitro binding, and colocalization mapping Apoptin to the C-terminal/pDED region of HIPPI\",\n      \"pmids\": [\"12745083\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional reconstitution of the Apoptin-HIPPI interaction\", \"Significance for apoptosis or ciliary function unresolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Placed HIPPI-induced cell death in a defined caspase cascade engaging both extrinsic and intrinsic pathways.\",\n      \"evidence\": \"GFP-HIPPI overexpression with caspase activity, Bid cleavage, and mitochondrial cytochrome c/AIF release readouts\",\n      \"pmids\": [\"16364650\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Based on overexpression rather than endogenous protein\", \"Causal ordering of caspase-1 vs caspase-8 activation not fully resolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Revealed a transcriptional arm of HIPPI function by showing its pDED directly binds caspase promoter DNA to upregulate caspase expression.\",\n      \"evidence\": \"EMSA, fluorescence quenching, ChIP, and luciferase reporter assays mapping HIPPI binding to a caspase-1 upstream sequence\",\n      \"pmids\": [\"17173859\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab; in vivo physiological role of promoter binding not established\", \"How a cytoplasmic adaptor accesses chromatin unaddressed in this study\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined an essential ciliary developmental role by demonstrating that HIPPI/IFT57 loss disrupts node cilia, left-right patterning, and Shh signaling.\",\n      \"evidence\": \"Hippi knockout mouse with SEM of node cilia, in situ hybridization of Shh targets, and immunohistochemistry\",\n      \"pmids\": [\"17027958\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic link between IFT57 and Shh transduction not dissected here\", \"Relationship between ciliary and apoptotic functions unresolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identified Homer1c as a partner that antagonizes HIPPI-induced neuronal apoptosis.\",\n      \"evidence\": \"Yeast two-hybrid and primary striatal neuron apoptosis assays with HIPPI-binding-domain deletion mutants\",\n      \"pmids\": [\"17107665\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of protection not defined\", \"Endogenous relevance in disease context untested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Pinpointed the specific promoter motif recognized by the HIPPI pDED, establishing sequence-specific DNA binding.\",\n      \"evidence\": \"EMSA with mutated promoter sequences and luciferase reporter assays in GFP-Hippi HeLa cells\",\n      \"pmids\": [\"17623017\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Structural basis of motif recognition not determined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified Rybp/DEDAF as a cofactor required for HIPPI-mediated caspase-8 apoptosis.\",\n      \"evidence\": \"Co-IP, caspase-8 apoptosis assays with genetic modulation, and neuronal colocalization\",\n      \"pmids\": [\"17874297\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether Rybp directly bridges HIPPI to caspase-8 not resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined IFT57's biochemical role within the IFT particle as required for IFT20 incorporation and kinesin-II release.\",\n      \"evidence\": \"Reciprocal Co-IP from zebrafish ift57 mutant vs wild-type extracts plus photoreceptor phenotyping\",\n      \"pmids\": [\"18492793\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of ATP-dependent kinesin dissociation not biochemically reconstituted\", \"IFT remains partially functional, leaving IFT57's precise contribution graded\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified BLOC1S2 as a HIPPI-specific (not HIP-1-binding) partner that promotes mitochondrial apoptotic sensitization.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, colocalization, and apoptosis sensitization assays in glioblastoma cells\",\n      \"pmids\": [\"18188704\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect link to mitochondrial apoptosis machinery unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Resolved how the cytoplasmic HIPPI reaches the nucleus and identified the catalytic-like residue for promoter binding.\",\n      \"evidence\": \"HIP-1 knockdown, NLS mutants, nuclear Co-IP, and R393E mutagenesis with reporter assays\",\n      \"pmids\": [\"19934260\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Composition of the nuclear transcription complex incompletely defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Extended HIPPI's transcriptional targets to REST/NRSF, linking nuclear HIPPI to neuronal gene repression relevant to Huntington disease.\",\n      \"evidence\": \"ChIP, luciferase reporter, HIP-1 NLS/knockdown manipulation, and RT-PCR of REST targets in a HD cell model\",\n      \"pmids\": [\"21832040\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance to HD neurodegeneration not established\", \"Single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established IFT57 as a human ciliopathy gene by linking a hypomorphic mutation to reduced IFT and Shh signaling.\",\n      \"evidence\": \"Exome sequencing, homozygosity mapping, and ciliary transport/Shh assays in patient fibroblasts\",\n      \"pmids\": [\"27060890\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single family report\", \"Genotype-phenotype mechanism in skeletal tissue not detailed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Clarified that IFT57 is not an essential structural bridge but instead stabilizes the IFT particle and transports specific motility cargoes.\",\n      \"evidence\": \"Chlamydomonas ift57-1 mutant flagellar proteomics, IFT motility imaging, and waveform analysis\",\n      \"pmids\": [\"28104816\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of cargo selectivity unknown\", \"Single lab; conservation of role across species inferred\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated cell-type-specific requirement for IFT57 in ciliogenesis through variant rescue in distinct knockout cell lines.\",\n      \"evidence\": \"IFT57-KO RPE1 and mIMCD3 cells with exogenous p.(Val397Glu) variant rescue and anterograde IFT assays\",\n      \"pmids\": [\"40273360\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of cell-type-specific dependence unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How IFT57's ciliary transport role and its HIP-1-dependent apoptotic/transcriptional role are coordinated within a single cell, and whether they share regulatory inputs, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No study integrates the ciliary and apoptotic functions mechanistically\", \"No high-resolution structure of the IFT57 pDED-HIP-1 complex with functional validation\", \"Endogenous physiological balance between the two roles undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [4, 5, 6]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [4, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [2, 3, 14]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 10]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 13]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 13]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"complexes\": [\n      \"IFT complex B (IFT-B2)\",\n      \"HIPPI-HIP-1-procaspase-8 complex\"\n    ],\n    \"partners\": [\n      \"HIP-1\",\n      \"IFT20\",\n      \"procaspase-8\",\n      \"RYBP\",\n      \"BLOC1S2\",\n      \"HOMER1\",\n      \"Apoptin\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}