| 2002 |
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. |
Co-immunoprecipitation, yeast two-hybrid, cell-based apoptosis assays, subcellular localization studies |
Nature cell biology |
High |
11788820
|
| 2008 |
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. |
Co-immunoprecipitation from zebrafish whole-animal extracts (ift57 mutants vs. wild-type), phenotypic analysis of ift57 and ift88 zebrafish mutants, immunohistochemistry |
Journal of cell science |
High |
18492793
|
| 2006 |
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. |
Hippi knockout mouse generation, immunohistochemistry, in situ hybridization for Shh target genes, scanning electron microscopy of node cilia |
Developmental biology |
High |
17027958
|
| 2017 |
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. |
Analysis of Chlamydomonas ift57-1 mutant: flagellar protein composition by mass spectrometry/immunoblot, IFT motility imaging, flagellar waveform analysis |
Journal of cell science |
Medium |
28104816
|
| 2006 |
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. |
EMSA, fluorescence quenching, chromatin immunoprecipitation (ChIP), luciferase reporter assay in HeLa and Neuro2A cells |
Biochemical and biophysical research communications |
Medium |
17173859
|
| 2007 |
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. |
EMSA with mutated promoter sequences, luciferase reporter assay with mutant promoters in GFP-Hippi-expressing HeLa cells |
The FEBS journal |
Medium |
17623017
|
| 2009 |
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. |
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 |
Nucleic acids research |
Medium |
19934260
|
| 2011 |
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. |
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 |
The Journal of biological chemistry |
Medium |
21832040
|
| 2003 |
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. |
Yeast two-hybrid screen, in vitro binding assay, co-localization by fluorescence microscopy, domain mapping |
Biochemical and biophysical research communications |
Medium |
12745083
|
| 2007 |
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. |
Co-immunoprecipitation, apoptosis assays (cell death quantification with caspase-8 readouts), immunofluorescence co-localization in mouse brain sections |
Apoptosis |
Medium |
17874297
|
| 2005 |
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. |
GFP-HIPPI overexpression in HeLa and Neuro2A cells; caspase activity assays, cytochrome c/AIF release by fractionation and immunoblot, nuclear fragmentation quantification |
Neurobiology of disease |
Medium |
16364650
|
| 2008 |
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. |
Yeast two-hybrid screen, co-immunoprecipitation, subcellular colocalization (immunofluorescence), apoptosis sensitization assays |
Apoptosis |
Medium |
18188704
|
| 2006 |
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). |
Yeast two-hybrid, primary neuron culture apoptosis assays with Homer1c co-expression and deletion mutants |
Biochemical and biophysical research communications |
Medium |
17107665
|
| 2016 |
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. |
Exome sequencing, homozygosity mapping, splicing assay, ciliary transport assay and Shh signaling measurement in patient-derived fibroblasts |
Clinical genetics |
Medium |
27060890
|
| 2025 |
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. |
Patient fibroblast analysis, IFT57-KO RPE1 and mIMCD3 cell lines, exogenous variant rescue experiments, cilia structure/function and anterograde transport assays |
Human molecular genetics |
Medium |
40273360
|
| 2006 |
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. |
Protein expression, purification, and X-ray crystallography (preliminary crystallographic analysis) |
Acta crystallographica Section F |
Low |
17142908
|
| 2007 |
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. |
X-ray crystallography at 2.8 Å resolution, structural modeling |
Journal of molecular biology |
Medium |
18155047
|