HTT

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0022008 neurogenesis	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: HTT is required in vivo for mammalian neurogenesis, including correct mitotic spindle orientation in cortical progenitors of the ventricular zone. The IBA neurogenesis annotation is consistent with this role, but it is a broad developmental/pleiotropic process rather than HTT's direct molecular activity, so it is best retained as a non-core annotation. Reason: HTT is essential for embryonic and neural development, but neurogenesis per se is downstream of HTT's molecular scaffold/transport functions. Supporting Evidence: PMID:20696378 In vivo inactivation of huntingtin by RNAi or by ablation of the Hdh gene affects spindle orientation and cell fate of cortical progenitors of the ventricular zone in mouse embryos.
GO:0007417 central nervous system development	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: HTT is required for embryonic CNS development and ciliogenesis in ependymal cells; loss of Htt causes defective neural progenitor spindle orientation, hydrocephalus and impaired CSF flow. The term is correct but broad and developmental, so kept as non-core. Reason: CNS development is a downstream consequence of HTT's scaffold and trafficking functions, not the direct molecular function. Supporting Evidence: PMID:21985783 In mice, deletion of Htt in ependymal cells led to PCM1 mislocalization, alteration of the cilia layer, and hydrocephalus.
GO:0030424 axon	IBA GO_REF:0000033	ACCEPT	Summary: HTT is well documented in axons where it scaffolds bidirectional vesicle (BDNF, autophagosome, endolysosome) transport on microtubules together with dynein/dynactin, HAP1 and kinesin-1. Axonal localization is a core part of HTT biology in neurons. Reason: Axon localization is supported by direct immunohistochemistry in human and rat brain neurons and by extensive functional studies of axonal vesicle transport. Supporting Evidence: PMID:7748555 Immunohistochemistry in human and rat brain revealed widespread cytoplasmic labeling of huntingtin within neurons, particularly cell bodies and dendrites file:human/HTT/HTT-deep-research-falcon.md A core concept in HTT biology is that it acts as a scaffold that recruits or coordinates motor/adaptor proteins on cargoes to support bidirectional axonal transport.
GO:0030425 dendrite	IBA GO_REF:0000033	ACCEPT	Summary: HTT is present in dendrites of neurons where it associates with vesicle membranes; consistent with its role as a neuronal cytoplasmic vesicle-associated scaffold. Reason: Dendritic localization is directly supported by immunohistochemistry in human and rat brain. Supporting Evidence: PMID:7748555 Immunohistochemistry in human and rat brain revealed widespread cytoplasmic labeling of huntingtin within neurons, particularly cell bodies and dendrites
GO:0031410 cytoplasmic vesicle	IBA GO_REF:0000033	ACCEPT	Summary: HTT associates with cytoplasmic vesicles (synaptic, BDNF, endosomal, autophagosomal) and is recovered in vesicle-enriched subcellular fractions; this is a long-established and core localization. Reason: Vesicle association is one of the most robustly supported aspects of HTT biology and underpins its scaffold role in vesicular transport and selective autophagy. Supporting Evidence: PMID:7748555 The ubiquitous cytoplasmic distribution of huntingtin in neurons and its association with vesicles suggest that huntingtin may have a role in vesicle trafficking.
GO:0047496 vesicle transport along microtubule	IBA GO_REF:0000033	ACCEPT	Summary: HTT directly binds dynein intermediate chain and the dynactin p150Glued subunit and is required for microtubule-based vesicle motility. This is a core HTT process annotation. Reason: Multiple independent experimental studies demonstrate that HTT facilitates dynein/dynactin- and kinesin-1-mediated vesicle transport along microtubules. Supporting Evidence: PMID:17548833 Antibodies to Htt inhibited vesicular transport along microtubules, suggesting that Htt facilitates dynein-mediated vesicle motility. PMID:18615096 When phosphorylated, huntingtin recruits kinesin-1 to the dynactin complex on vesicles and MTs.
GO:0048489 synaptic vesicle transport	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: HTT is present at synaptic compartments and contributes to vesicle trafficking there, but the precisely characterized HTT-dependent cargoes are BDNF, autophagosomes and endolysosomes rather than canonical synaptic vesicles. Kept as a non-core annotation. Reason: Synaptic vesicle transport is consistent with HTT's neuronal vesicle scaffold role but is not the most characterised cargo class; vesicle transport along microtubules is the more general and better supported process term. Supporting Evidence: PMID:7748555 The same protein species was detected in human and rat cortex synaptosomes and in sucrose density gradients of vesicle-enriched fractions, where huntingtin immunoreactivity overlapped with the distribution of vesicle membrane proteins (SV2, transferrin receptor, and synaptophysin).
GO:1905289 regulation of CAMKK-AMPK signaling cascade	IBA GO_REF:0000033	MARK AS OVER ANNOTATED	Summary: Although AMPK-alpha1 is aberrantly activated and translocates to the nucleus in HD striatal neurons, the relevant evidence describes a mutant HTT (mHTT) gain-of-function neurodegenerative pathway in the striatum rather than a normal regulatory role of HTT in the CAMKK-AMPK signalling cascade. The term is too broad and is best marked as over-annotated for HTT's core function. Reason: The original supporting evidence describes mHTT-driven AMPK misregulation as a disease mechanism, not a normal regulatory activity of wild-type HTT on the CAMKK-AMPK cascade. Supporting Evidence: PMID:21768291 Overactivation of AMPK in the striatum caused brain atrophy, facilitated neuronal loss, and increased formation of Htt aggregates in a transgenic mouse model (R6/2) of HD.
GO:0005634 nucleus	IEA GO_REF:0000120	ACCEPT	Summary: A regulated nuclear pool of HTT exists; HTT contains a conserved nuclear export signal and shuttles between cytoplasm and nucleus. Although the dominant localization is cytoplasmic, the IEA annotation to nucleus is supported. Reason: Direct immunofluorescence and shuttling experiments show a nuclear pool of HTT under basal and stress conditions. Supporting Evidence: PMID:15654337 Here we report that N-terminal htt shuttles between the cytoplasm and nucleus in a Ran GTPase-independent manner. PMID:12783847 Huntingtin contains a highly conserved nuclear export signal.
GO:0005737 cytoplasm	IEA GO_REF:0000120	ACCEPT	Summary: HTT is predominantly a cytoplasmic protein in neurons and other cells; cytoplasmic localization is the dominant and well-documented compartment. Reason: Direct biochemical fractionation and immunohistochemistry in human and rat brain support cytoplasmic localization as the primary compartment for HTT. Supporting Evidence: PMID:7748555 Huntingtin is a cytoplasmic protein associated with vesicles in human and rat brain neurons.
GO:0005769 early endosome	IEA GO_REF:0000044	ACCEPT	Summary: HTT-HAP40 forms a Rab5 effector complex on early endosomes that regulates their cytoskeletal association and motility. Early endosome localization is a core HTT compartment. Reason: Direct biochemical and microscopy evidence places HTT on early endosomes as part of a HAP40/Rab5 complex. Supporting Evidence: PMID:16476778 HAP40 mediates the recruitment of Htt by Rab5 onto early endosomes.
GO:0005776 autophagosome	IEA GO_REF:0000044	ACCEPT	Summary: HTT is recruited to autophagic membranes, interacts with LC3 and p62, and is required for selective macroautophagy; autophagosome localization is core. Reason: HTT's N17 membrane-targeting helix specifically targets autophagic vesicles, and HTT scaffolds the assembly of p62/LC3 cargo receptors on forming autophagosomes. Supporting Evidence: PMID:17704510 Huntingtin vesicular interaction mediated by 1-18 is specific to late endosomes and autophagic vesicles. PMID:25686248 Huntingtin physically interacts with the autophagy cargo receptor p62 to facilitate its association with the integral autophagosome component LC3 and with Lys-63-linked ubiquitin-modified substrates.
GO:0006915 apoptotic process	IEA GO_REF:0000043	REMOVE	Summary: Wild-type HTT is broadly anti-apoptotic rather than a positive component of the apoptotic process. The unspecified "apoptotic process" term derived from keyword mapping is too generic and directionally ambiguous; specific negative regulation annotations capture the relevant biology better. Reason: Generic apoptotic process is uninformative for HTT, and GO_REF:0000043 keyword-derived annotations on cellular organisms have been retracted. The anti-apoptotic role is captured by the more specific GO:0043066 / GO:2001237 annotations also present here.
GO:0007017 microtubule-based process	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	Summary: HTT participates in microtubule-based processes (motor-driven vesicle transport, mitotic spindle orientation, beta-tubulin binding). The general parent term is correct but uninformative; the more specific vesicle-transport-along-microtubule and establishment-of-mitotic-spindle-orientation annotations capture the activity better. Reason: Parent term is too general given the available specific microtubule-based process annotations for HTT in the same review.
GO:0009966 regulation of signal transduction	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	Summary: Extremely general process term that does not convey any specific HTT function. ARBA machine-learning IEA annotations to this high-level term are uninformative for a multifunctional scaffold. Reason: Too generic to add curatorial value; HTT does not have a defined signal transduction activity, only context-specific pathway-modulating interactions.
GO:0030424 axon	IEA GO_REF:0000117	ACCEPT	Summary: Duplicate of the IBA-supported axon annotation above. Accepted as a core localization. Reason: Axonal localization of HTT is well established in neurons. Supporting Evidence: PMID:7748555 Immunohistochemistry in human and rat brain revealed widespread cytoplasmic labeling of huntingtin within neurons, particularly cell bodies and dendrites
GO:0031410 cytoplasmic vesicle	IEA GO_REF:0000120	ACCEPT	Summary: Duplicate of the IBA-supported cytoplasmic vesicle annotation above. Accepted as a core HTT localization. Reason: Vesicle association of HTT is one of its most robust localizations. Supporting Evidence: PMID:7748555 The ubiquitous cytoplasmic distribution of huntingtin in neurons and its association with vesicles suggest that huntingtin may have a role in vesicle trafficking.
GO:0043066 negative regulation of apoptotic process	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Wild-type HTT is anti-apoptotic in several stress contexts (e.g., prevents caspase-mediated Pak2 cleavage). Negative regulation of apoptosis is a true HTT biological process but is a downstream, context-dependent role rather than its core scaffold function; kept as non-core. Reason: HTT's anti-apoptotic effect is well supported but is mediated through HTT's binding to and stabilisation of partner proteins (e.g., Pak2), not through a direct apoptosis-regulating activity. Supporting Evidence: PMID:19240112 huntingtin exerts anti-apoptotic effects by binding to Pak2, which reduces the abilities of caspase-3 and caspase-8 to cleave Pak2 and convert it into a mediator of cell death.
GO:0045202 synapse	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: HTT is detected in synaptosomal fractions and at pre- and post-synaptic cytosol. Synapse is a valid but non-core localization, since HTT's scaffold function is exerted broadly along the neuron, not specifically at the synapse. Reason: Synapse localization is consistent with HTT's vesicle scaffold role in neurons but represents a downstream compartment rather than a core function-defining site. Supporting Evidence: PMID:7748555 The same protein species was detected in human and rat cortex synaptosomes and in sucrose density gradients of vesicle-enriched fractions
GO:0005515 protein binding	IPI PMID:10823891 The Huntington's disease protein interacts with p53 and CREB...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation reflecting an IPI to p53/CBP. A specific p53 binding annotation (GO:0002039) is independently present from the same paper, which is much more informative; the generic "protein binding" entry is over-annotation. Reason: CLAUDE.md curation guidance: avoid generic "protein binding"; the specific p53 binding (GO:0002039) annotation captures the actual interaction.
GO:0005515 protein binding	IPI PMID:11137014 FIP-2, a coiled-coil protein, links Huntingtin to Rab8 and m...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation derived from the FIP-2/Rab8 interaction; uninformative on its own. The actual finding (HTT as a Rab8-associated scaffold for morphogenesis) is better captured by future Rab effector annotations rather than a bare "protein binding" entry. Reason: Generic protein binding from interactome data is uninformative per project guidelines.
GO:0005515 protein binding	IPI PMID:11988536 Sp1 and TAFII130 transcriptional activity disrupted in early...	MARK AS OVER ANNOTATED	Summary: Generic protein binding annotation derived from Sp1/TAFII130 interaction in HD context. Disease-context interaction; not core HTT function and uninformative as a bare "protein binding" term. Reason: Generic protein binding; disease/pathology context.
GO:0005515 protein binding	IPI PMID:12873381 Huntingtin and huntingtin-associated protein 1 influence neu...	MARK AS OVER ANNOTATED	Summary: Generic protein binding reflecting the HAP1/InsP3R1 interaction. Captured better by the GO:0044325 (transmembrane transporter binding) and GO:0050850 (positive regulation of calcium-mediated signaling) annotations from the same paper. Reason: Specific functional annotations (calcium signaling, transporter binding) from the same paper already represent this interaction.
GO:0005515 protein binding	IPI PMID:15383276 A protein interaction network links GIT1, an enhancer of hun...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from a high-throughput interaction network screen identifying GIT1 as a polyQ-aggregation modifier. Reason: HTP interactome screen producing only a generic "protein binding" annotation; uninformative.
GO:0005515 protein binding	IPI PMID:15603740 Huntingtin-interacting protein HIP14 is a palmitoyl transfer...	MARK AS OVER ANNOTATED	Summary: Generic protein binding reflecting the HTT-HIP14 interaction, which establishes HTT as a palmitoylated substrate of HIP14 (ZDHHC17). Useful biology but better captured by the zDHHC17-recognition motif annotation (GO:0026198635) and by future palmitoylation-substrate annotations. Reason: Generic protein binding from interaction screen; substrate relationship better captured elsewhere. Supporting Evidence: PMID:15603740 HIP14 shows remarkable substrate specificity for neuronal proteins, including SNAP-25, PSD-95, GAD65, synaptotagmin I, and htt.
GO:0005515 protein binding	IPI PMID:16115810 Ataxin-2 and huntingtin interact with endophilin-A complexes...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from interactome data (ataxin-2 / endophilin-A complex). Disease/aggregation context. Reason: Generic protein binding from interaction screens; uninformative.
GO:0005515 protein binding	IPI PMID:16169070 A human protein-protein interaction network: a resource for ...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from a global Y2H-based human interactome proteome resource. High-throughput screen. Reason: Generic protein binding from large-scale interactome data.
GO:0005515 protein binding	IPI PMID:17161366 Structural insights into the specific binding of huntingtin ...	MARK AS OVER ANNOTATED	Summary: Generic protein binding reflecting structural studies of HTT polyproline region with SH3/WW domains. The biologically informative annotation here would be SH3/WW-domain protein binding; the bare "protein binding" entry is uninformative. Reason: Generic protein binding; more specific term would be more informative.
GO:0005515 protein binding	IPI PMID:17500595 Huntingtin interacting proteins are genetic modifiers of neu...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from a genetic modifier/interactor screen. Reason: Generic protein binding from large-scale interaction data.
GO:0005515 protein binding	IPI PMID:17548833 Huntingtin facilitates dynein/dynactin-mediated vesicle tran...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from the dynein intermediate chain (DIC) study. The same paper supports the more informative GO:0045505 (dynein intermediate chain binding) annotation, also present in this review. Reason: Specific GO:0045505 dynein intermediate chain binding annotation captures this interaction informatively. Supporting Evidence: PMID:17548833 Htt and dynein intermediate chain interact directly
GO:0005515 protein binding	IPI PMID:18192679 Huntingtin-associated protein-1 is a modifier of the age-at-...	MARK AS OVER ANNOTATED	Summary: Generic protein binding linked to the HAP1 age-at-onset modifier study; HAP1 interaction is one of the core HTT interactions but a bare protein binding annotation does not capture this. Reason: Generic protein binding; HAP1 interaction better represented through dynactin/dynein motor coupling annotations.
GO:0005515 protein binding	IPI PMID:18615096 Huntingtin phosphorylation acts as a molecular switch for an...	MARK AS OVER ANNOTATED	Summary: Generic protein binding reflecting HTT-kinesin-1/dynactin interaction. The functional content of this paper is captured much better by the dynactin and dynein binding and vesicle transport annotations. Reason: Generic protein binding; specific motor and transport annotations are more informative. Supporting Evidence: PMID:18615096 When phosphorylated, huntingtin recruits kinesin-1 to the dynactin complex on vesicles and MTs.
GO:0005515 protein binding	IPI PMID:19240112 Huntingtin promotes cell survival by preventing Pak2 cleavag...	MARK AS OVER ANNOTATED	Summary: Generic protein binding reflecting the HTT-Pak2 interaction underlying HTT's anti-apoptotic activity. Better captured by the specific GO:2001237 negative regulation of extrinsic apoptotic signalling annotation also present. Reason: Functional annotation for the same interaction already exists.
GO:0005515 protein binding	IPI PMID:20417604 The selective macroautophagic degradation of aggregated prot...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from Alfy/WDFY3 aggrephagy paper. Biology is captured by aggrephagy-related annotations. Reason: Generic protein binding; specific autophagy annotations exist.
GO:0005515 protein binding	IPI PMID:22119730 α-Synuclein modifies huntingtin aggregation in living cells.	MARK AS OVER ANNOTATED	Summary: Generic protein binding from alpha-synuclein/HTT aggregation study. Disease/aggregation context. Reason: Generic protein binding from interaction in aggregation context.
GO:0005515 protein binding	IPI PMID:22835334 Replacement of charged and polar residues in the coiled-coil...	MARK AS OVER ANNOTATED	Summary: Generic protein binding reflecting HTT-HIP1 interaction (HIP1 coiled-coil mutagenesis paper). Reason: Generic protein binding from interaction screen; HIP1 binding better captured under endocytic/clathrin scaffolding contexts.
GO:0005515 protein binding	IPI PMID:23275563 Development and application of a DNA microarray-based yeast ...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from a DNA-microarray Y2H interaction screen platform paper. Reason: HTP screen producing only generic protein binding annotation.
GO:0005515 protein binding	IPI PMID:23303669 Chaperone-like activity of high-mobility group box 1 protein...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from HMGB1/polyQ aggregate chaperone study. Reason: Generic protein binding in aggregation context.
GO:0005515 protein binding	IPI PMID:24705354 The palmitoyl acyltransferase HIP14 shares a high proportion...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from the HIP14/HTT shared interactome study. Reason: Generic protein binding from interactome data; uninformative.
GO:0005515 protein binding	IPI PMID:25686248 Huntingtin functions as a scaffold for selective macroautoph...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from the Rui et al. selective autophagy scaffold paper. This paper's biology is much better represented by the specific kinase binding (ULK1) and positive regulation of mitophagy/lipophagy/aggrephagy annotations also present. Reason: Functional ULK1 binding and selective autophagy annotations already capture the relevant biology. Supporting Evidence: PMID:25686248 Maximal activation of selective autophagy during stress is attained by the ability of Huntingtin to bind ULK1, a kinase that initiates autophagy, which releases ULK1 from negative regulation by mTOR.
GO:0005515 protein binding	IPI PMID:25959826 Quantitative interaction proteomics of neurodegenerative dis...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from quantitative interaction proteomics screen of neurodegenerative disease proteins. Reason: HTP interaction proteomics yielding only generic protein binding.
GO:0005515 protein binding	IPI PMID:26637326 ENC1 Modulates the Aggregation and Neurotoxicity of Mutant H...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from the ENC1/HTT aggregation study under ER stress. Reason: Generic protein binding in disease/aggregation context.
GO:0005515 protein binding	IPI PMID:28445460 Polyglutamine tracts regulate beclin 1-dependent autophagy.	MARK AS OVER ANNOTATED	Summary: Generic protein binding from the beclin1/HTT autophagy regulation study; the more informative biology is HTT's contribution to autophagy regulation. Reason: Generic protein binding; specific autophagy regulation annotations exist for HTT.
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from a large-scale BioPlex-style interactome study. Reason: Generic protein binding from a global proteome interactome.
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from a neurodegenerative disease interactome mapping study. Reason: Generic protein binding from large-scale interactome screen.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from BioPlex 3.0 proteome-scale interactome. Reason: Generic protein binding from large-scale interactome screen.
GO:0005515 protein binding	IPI PMID:34524948 Global Proximity Interactome of the Human Macroautophagy Pat...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from the global proximity interactome of the macroautophagy pathway. The autophagy-scaffold function of HTT is well captured by the specific autophagy annotations in this review. Reason: HTP proximity interactome producing generic protein binding; specific autophagy annotations exist.
GO:0005515 protein binding	IPI PMID:9285789 Huntingtin-associated protein 1 (HAP1) binds to a Trio-like ...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from a HAP1/Trio-domain Y2H paper. Reason: Generic protein binding from interaction screen.
GO:0005515 protein binding	IPI PMID:9668110 A human HAP1 homologue. Cloning, expression, and interaction...	MARK AS OVER ANNOTATED	Summary: Generic protein binding reflecting cloning of human HAP1 as a HTT-interacting protein. The HAP1 interaction is core HTT biology but a bare protein binding annotation is not informative. Reason: Generic protein binding; HAP1 binding is captured implicitly through HTT's motor/cargo annotations.
GO:0005515 protein binding	IPI PMID:9798945 Association of HAP1 isoforms with a unique cytoplasmic struc...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from a HAP1-isoform localization paper. Reason: Generic protein binding from immunolocalization study.
GO:0042802 identical protein binding	IPI PMID:19487684 Distinct conformations of in vitro and in vivo amyloids of h...	KEEP AS NON CORE	Summary: HTT exon-1 polyQ fragments self-assemble into amyloid fibers in vitro and in vivo. Identical protein binding here reflects polyQ-mediated self-aggregation, a pathological/aggregation phenotype rather than a normal HTT molecular function. Reason: Self-association of HTT exon-1 is well documented in aggregation studies but represents a disease-context oligomerization rather than HTT's evolved function. Supporting Evidence: PMID:19487684 Distinct conformations of in vitro and in vivo amyloids of huntingtin-exon1 show different cytotoxicity.
GO:0042802 identical protein binding	IPI PMID:22119730 α-Synuclein modifies huntingtin aggregation in living cells.	KEEP AS NON CORE	Summary: Identical protein binding inferred from polyQ aggregation cross-modulation studies (alpha-synuclein/HTT). Aggregation context. Reason: Aggregation-context self-association rather than core physiological function.
GO:0042802 identical protein binding	IPI PMID:22854022 SERF protein is a direct modifier of amyloid fiber assembly.	KEEP AS NON CORE	Summary: Identical protein binding inferred from a SERF/amyloid fibre modifier study. Aggregation/disease context. Reason: Aggregation-context self-association rather than normal function.
GO:0042802 identical protein binding	IPI PMID:23275563 Development and application of a DNA microarray-based yeast ...	MARK AS OVER ANNOTATED	Summary: Identical protein binding from a yeast two-hybrid screening platform paper. Reason: Methods-paper Y2H hit; uninformative for biological function.
GO:0042802 identical protein binding	IPI PMID:25848931 siRNA screen identifies QPCT as a druggable target for Hunti...	KEEP AS NON CORE	Summary: Identical protein binding from a QPCT siRNA screen for HTT aggregation modulators. Disease/aggregation context. Reason: Disease-context aggregation modifier evidence.
GO:0050850 positive regulation of calcium-mediated signaling	IDA PMID:12873381 Huntingtin and huntingtin-associated protein 1 influence neu...	KEEP AS NON CORE	Summary: HTT, together with HAP1, sensitises InsP3R1 to InsP3 in striatal medium spiny neurons. The effect is most pronounced for mHTT but the wild-type HTT-HAP1-InsP3R1 complex is also functionally relevant; kept as a non-core neuron-specific signalling modulation. Reason: Calcium signalling modulation is a downstream consequence of HTT-HAP1 scaffolding on InsP3R1, not a core molecular activity. Supporting Evidence: PMID:12873381 We show that an InsP3R1-HAP1A-Htt ternary complex is formed in vitro and in vivo.
GO:0005654 nucleoplasm	IDA GO_REF:0000052	KEEP AS NON CORE	Summary: Human Protein Atlas-style immunofluorescence shows HTT signal in the nucleoplasm consistent with HTT's known nuclear shuttling pool. Accepted but minor relative to cytoplasmic localization. Reason: Nuclear/nucleoplasmic pool of HTT exists but the dominant compartment for HTT's functions is the cytoplasm.
GO:0005829 cytosol	IDA GO_REF:0000052	ACCEPT	Summary: Human Protein Atlas immunofluorescence supports cytosolic localization, consistent with the long-established cytoplasmic distribution of HTT in neurons and other cell types. Reason: Cytosolic localization is a core compartment for HTT. Supporting Evidence: PMID:7748555 Huntingtin is a cytoplasmic protein associated with vesicles in human and rat brain neurons.
GO:1905291 positive regulation of CAMKK-AMPK signaling cascade	IMP PMID:21768291 Nuclear translocation of AMPK-alpha1 potentiates striatal ne...	MARK AS OVER ANNOTATED	Summary: The Ju et al. paper describes mHTT-driven nuclear AMPK-alpha1 activation as a striatal neurotoxic pathway, not a normal positive regulatory function of HTT on the CAMKK-AMPK cascade. Reason: Disease-context gain-of-function inference; not a normal HTT molecular activity. Supporting Evidence: PMID:21768291 aberrant activation of AMPK-α1 in the nuclei of striatal cells represents a new toxic pathway induced by mHtt.
GO:0004721 phosphoprotein phosphatase activity	IMP PMID:21562226 Dictyostelium huntingtin controls chemotaxis and cytokinesis...	REMOVE	Summary: Annotation derived from a Dictyostelium HTT chemotaxis paper suggesting HTT regulates myosin II phosphorylation; this does not establish that mammalian HTT itself has phosphoprotein phosphatase activity. HTT lacks a catalytic phosphatase domain and is universally described as a non-enzymatic scaffold/adaptor. Reason: No structural or biochemical evidence for an intrinsic phosphatase activity of HTT; cross-species IMP overinterprets an indirect phosphorylation regulation phenotype. Supporting Evidence: file:human/HTT/HTT-deep-research-falcon.md HTT is not an enzyme or transporter; its "primary function" is best captured as a scaffold/adaptor coordinating cargo recognition (including ubiquitin-associated cargo), vesicular trafficking, and autophagy–lysosome pathway dynamics
GO:0099523 presynaptic cytosol	IEP PMID:7748555 Huntingtin is a cytoplasmic protein associated with vesicles...	KEEP AS NON CORE	Summary: HTT is recovered in cortical synaptosomes; presynaptic cytosol localization is consistent with this fractionation. Reason: Synaptic-compartment localization is a downstream consequence of HTT's neuronal vesicle scaffold role. Supporting Evidence: PMID:7748555 The same protein species was detected in human and rat cortex synaptosomes
GO:0099523 presynaptic cytosol	IDA PMID:7748555 Huntingtin is a cytoplasmic protein associated with vesicles...	KEEP AS NON CORE	Summary: Duplicate of the IEP synaptic cytosol annotation above. Reason: Same supporting evidence as the IEP annotation; non-core. Supporting Evidence: PMID:7748555 The same protein species was detected in human and rat cortex synaptosomes
GO:0099524 postsynaptic cytosol	IDA PMID:7748555 Huntingtin is a cytoplasmic protein associated with vesicles...	KEEP AS NON CORE	Summary: HTT immunoreactivity is found at dendritic/postsynaptic sites in brain neurons. Reason: Postsynaptic cytosol is a downstream compartment, consistent with dendrite localization but not core function-defining. Supporting Evidence: PMID:7748555 Immunohistochemistry in human and rat brain revealed widespread cytoplasmic labeling of huntingtin within neurons, particularly cell bodies and dendrites
GO:1901526 positive regulation of mitophagy	IMP PMID:25686248 Huntingtin functions as a scaffold for selective macroautoph...	ACCEPT	Summary: HTT positively regulates selective autophagy of damaged mitochondria. Strongly supported by both the Rui et al. 2015 scaffold paper and the Fote et al. 2024 PNAS demonstration that HTT knockout reduces basal mitochondrial protein clearance via lysosomes. Core HTT process annotation. Reason: Multiple independent studies show HTT is required for efficient selective mitochondrial autophagy. Supporting Evidence: PMID:25686248 functions as a scaffold protein for selective macroautophagy PMID:39074279 HTT KO was associated with reduced abundance of mitochondrial proteins in the lysosome, indicating a potential compromise in basal mitophagy
GO:0005515 protein binding	IPI PMID:16476778 Huntingtin-HAP40 complex is a novel Rab5 effector that regul...	MARK AS OVER ANNOTATED	Summary: Generic protein binding reflecting the HAP40/Rab5 effector complex. Better captured by the early endosome localization annotation also present. Reason: Generic protein binding; specific HAP40/Rab5 effector relationship better represented through localization and Rab effector annotations.
GO:0005769 early endosome	IDA PMID:16476778 Huntingtin-HAP40 complex is a novel Rab5 effector that regul...	ACCEPT	Summary: HTT, together with HAP40, is recruited to early endosomes as a Rab5 effector. Core HTT localization. Reason: Direct biochemical and microscopy evidence places HTT on Rab5+ early endosomes via the HAP40 adaptor. Supporting Evidence: PMID:16476778 HAP40 mediates the recruitment of Htt by Rab5 onto early endosomes.
GO:0005522 profilin binding	IPI PMID:18573880 Phosphorylation of profilin by ROCK1 regulates polyglutamine...	KEEP AS NON CORE	Summary: HTT polyproline region binds profilin; relevant in part to the modulation of polyQ aggregation. Not part of HTT's core scaffold/transport function. Reason: Profilin binding is a specific molecular interaction that modulates aggregation but is not part of HTT's core conserved function.
GO:1905289 regulation of CAMKK-AMPK signaling cascade	IMP PMID:21768291 Nuclear translocation of AMPK-alpha1 potentiates striatal ne...	MARK AS OVER ANNOTATED	Summary: Same disease/gain-of-function evidence as the IBA-supported CAMKK-AMPK annotation; the Ju et al. paper describes mHTT-driven aberrant AMPK activation rather than normal HTT regulation of the cascade. Reason: Disease-context gain-of-function inference; not a normal HTT activity.
GO:0005515 protein binding	IPI PMID:29466333 The cryo-electron microscopy structure of huntingtin.	MARK AS OVER ANNOTATED	Summary: Generic protein binding reflecting HAP40-HTT structural interaction defined by cryo-EM. The HTT-HAP40 complex is a defining structural feature of HTT, but this is better captured by HAP40-specific annotations and by HTT's Rab5 effector role. Reason: Generic protein binding; HAP40 interaction is better captured through protein complex / Rab5 effector annotations. Supporting Evidence: PMID:29466333 HAP40 binds in a cleft and contacts the three HTT domains by hydrophobic and electrostatic interactions, thereby stabilizing the conformation of HTT.
GO:0048471 perinuclear region of cytoplasm	ISS GO_REF:0000024	ACCEPT	Summary: HTT shows perinuclear cytoplasmic localization in many cell types, especially around the centrosome (consistent with ciliogenesis HTT-HAP1-PCM1 evidence and microtubule binding). Supported by direct biochemistry showing HTT binds beta-tubulin and accumulates perinuclearly as a microtubule-bound pool. Reason: Perinuclear cytoplasmic localization is established by direct microtubule/beta-tubulin binding (PMID:11870213) and supports HTT's centrosome-related ciliogenesis and spindle orientation roles. Supporting Evidence: PMID:11870213 Perinuclear localization of huntingtin as a consequence of its binding to microtubules through an interaction with beta-tubulin: relevance to Huntington's disease.
GO:0005515 protein binding	IPI PMID:17947297 HYPK, a Huntingtin interacting protein, reduces aggregates a...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from the HYPK/HTT chaperone-like interaction study. Reason: Generic protein binding; HYPK interaction is a chaperone/aggregation modifier and not core HTT function.
GO:0005634 nucleus	IMP PMID:17947297 HYPK, a Huntingtin interacting protein, reduces aggregates a...	ACCEPT	Summary: Mutant N-terminal HTT with 40Qs accumulates in nuclear inclusions in Neuro2a cells; this is a disease/aggregation phenotype, not a normal HTT nuclear function. Accepted as consistent with the established existence of a normal nuclear HTT pool. Reason: Nuclear localization of HTT (a regulated nuclear pool) is well established by stronger evidence; this IMP observation is consistent.
GO:0005737 cytoplasm	IMP PMID:17947297 HYPK, a Huntingtin interacting protein, reduces aggregates a...	ACCEPT	Summary: Cytoplasmic localization of HTT N-terminal constructs in Neuro2a cells; consistent with the dominant cytoplasmic compartment. Reason: Cytoplasmic localization of HTT is robustly supported.
GO:0016234 inclusion body	IMP PMID:17947297 HYPK, a Huntingtin interacting protein, reduces aggregates a...	KEEP AS NON CORE	Summary: Mutant HTT-Q40 forms intracellular inclusion bodies in Neuro2a cells, a hallmark of HD pathology. Not core HTT function; kept as non-core to record the pathological compartment. Reason: Inclusion body localization is a disease/aggregation phenotype of mHTT, not a normal HTT localization.
GO:0031648 protein destabilization	IMP PMID:17947297 HYPK, a Huntingtin interacting protein, reduces aggregates a...	REMOVE	Summary: Evidence does not establish HTT as a positive regulator of protein destabilization; the paper actually describes HYPK as a chaperone that reduces HTT aggregates. The destabilization annotation is misleading and not supported as a HTT activity. Reason: The cited paper supports HYPK chaperone-mediated reduction of HTT aggregates, not a HTT protein-destabilization activity.
GO:0032991 protein-containing complex	IMP PMID:17947297 HYPK, a Huntingtin interacting protein, reduces aggregates a...	MARK AS OVER ANNOTATED	Summary: HTT is part of numerous protein-containing complexes; the annotation is correct but extremely general. Reason: Trivially true for HTT and uninformative as a top-level annotation.
GO:0043065 positive regulation of apoptotic process	IDA PMID:17947297 HYPK, a Huntingtin interacting protein, reduces aggregates a...	REMOVE	Summary: Mutant HTT-Q40 induces apoptosis in Neuro2a cells, but this reflects toxic gain-of-function by mHTT N-terminal fragments, not a normal pro-apoptotic activity of HTT. Wild-type HTT is broadly anti-apoptotic (see GO:2001237). Reason: Annotation reflects mHTT pathological toxicity, contradicting the well-established anti-apoptotic role of wild-type HTT.
GO:0048471 perinuclear region of cytoplasm	IMP PMID:17947297 HYPK, a Huntingtin interacting protein, reduces aggregates a...	ACCEPT	Summary: Perinuclear cytoplasmic localization in Neuro2a cells. Consistent with the established perinuclear/microtubule-bound pool of HTT. Reason: Consistent with direct microtubule/beta-tubulin-mediated perinuclear localization of HTT.
GO:0031072 heat shock protein binding	IPI PMID:21909508 Intrinsically disordered proteins as molecular shields.	KEEP AS NON CORE	Summary: Generic interaction of HTT with intrinsically disordered chaperone-like proteins; not a defining HTT molecular function. Reason: Heat shock protein binding is a chaperone-context interaction rather than a core HTT activity.
GO:0019900 kinase binding	IPI PMID:25686248 Huntingtin functions as a scaffold for selective macroautoph...	ACCEPT	Summary: HTT binds the autophagy-initiating kinase ULK1, releasing it from mTOR inhibition and activating selective autophagy. Kinase binding is a core molecular activity of HTT that underpins its scaffold role in selective autophagy. Reason: Direct interaction of HTT with ULK1 is well documented and is mechanistically central to HTT's autophagy-scaffold function. Supporting Evidence: PMID:25686248 Maximal activation of selective autophagy during stress is attained by the ability of Huntingtin to bind ULK1, a kinase that initiates autophagy, which releases ULK1 from negative regulation by mTOR.
GO:1904504 positive regulation of lipophagy	IMP PMID:25686248 Huntingtin functions as a scaffold for selective macroautoph...	ACCEPT	Summary: HTT acts as a scaffold for selective lipophagy, in line with its general role as a scaffold for ubiquitin-/p62-dependent selective autophagy. Core HTT process. Reason: Lipophagy is one of the selective autophagy modes scaffolded by HTT in the Rui et al. study. Supporting Evidence: PMID:25686248 Huntingtin functions as a scaffold for selective macroautophagy.
GO:1905337 positive regulation of aggrephagy	IMP PMID:25686248 Huntingtin functions as a scaffold for selective macroautoph...	ACCEPT	Summary: HTT scaffolds aggrephagy by linking p62-bound ubiquitinated aggregates to LC3 on autophagic membranes. Core HTT process. Reason: Aggrephagy is the most thoroughly characterised selective autophagy mode supported by HTT scaffolding. Supporting Evidence: PMID:25686248 Huntingtin physically interacts with the autophagy cargo receptor p62 to facilitate its association with the integral autophagosome component LC3 and with Lys-63-linked ubiquitin-modified substrates.
GO:0005515 protein binding	IPI PMID:26198635 Identification of a Novel Sequence Motif Recognized by the A...	MARK AS OVER ANNOTATED	Summary: Generic protein binding reflecting recognition of HTT by the ankyrin repeat domain of HIP14/HIP14L (ZDHHC17/ZDHHC13) palmitoyl acyltransferases. The substrate/recognition motif relationship is informative but the bare protein binding annotation is not. Reason: Generic protein binding; recognition by zDHHC17/13 is better captured under palmitoylation substrate annotations.
GO:0042297 vocal learning	IMP PMID:26436900 Human mutant huntingtin disrupts vocal learning in transgeni...	REMOVE	Summary: Annotation based on a transgenic songbird model expressing human mHTT showing disrupted vocal learning. This is a cross-species disease-model phenotype and does not represent a normal molecular function of human HTT in vocal learning; humans do not undergo vocal learning in the songbird sense. Reason: Annotation extrapolates a disease-model behavioural phenotype in songbirds to a normal HTT function; vocal learning is not a process applicable to wild-type HTT in humans.
GO:0005814 centriole	IDA PMID:21985783 Ciliogenesis is regulated by a huntingtin-HAP1-PCM1 pathway ...	ACCEPT	Summary: HTT is required for ciliogenesis through a HTT-HAP1-PCM1 pathway and localises with PCM1 at the pericentriolar/centriolar region. Core HTT localization with respect to its ciliogenesis function. Reason: Direct evidence that HTT regulates centrosomal protein delivery and that loss of HTT mislocalises PCM1 and impairs ciliogenesis. Supporting Evidence: PMID:21985783 WT HTT regulates ciliogenesis by interacting through huntingtin-associated protein 1 (HAP1) with pericentriolar material 1 protein (PCM1).
GO:0045724 positive regulation of cilium assembly	IMP PMID:21985783 Ciliogenesis is regulated by a huntingtin-HAP1-PCM1 pathway ...	ACCEPT	Summary: HTT positively regulates primary cilium assembly via the HTT-HAP1-PCM1 axis. Core HTT process. Reason: Direct in vivo and in vitro evidence: loss of Htt impairs retrograde PCM1 trafficking and reduces primary cilia formation; deletion in ependymal cells causes cilia layer alteration. Supporting Evidence: PMID:21985783 Loss of Htt in mouse cells impaired the retrograde trafficking of PCM1 and thereby reduced primary cilia formation.
GO:0044325 transmembrane transporter binding	IDA PMID:12873381 Huntingtin and huntingtin-associated protein 1 influence neu...	KEEP AS NON CORE	Summary: HTT (with HAP1) directly forms a complex with the InsP3R1 intracellular Ca2+ release channel; the receptor is a transmembrane channel/transporter on the ER. Annotation is biologically appropriate. Reason: InsP3R1 binding is a real, specific HTT interaction relevant to neuronal calcium signalling but represents a peripheral non-core function. Supporting Evidence: PMID:12873381 We show that an InsP3R1-HAP1A-Htt ternary complex is formed in vitro and in vivo.
GO:2001237 negative regulation of extrinsic apoptotic signaling pathway	IMP PMID:19240112 Huntingtin promotes cell survival by preventing Pak2 cleavag...	ACCEPT	Summary: HTT binds Pak2 and inhibits its caspase-3/8-mediated cleavage into the pro-apoptotic constitutively active fragment, thereby attenuating Fas/TNF-induced apoptosis. Specific and well supported anti-apoptotic activity of wild-type HTT. Reason: Specific mechanism (Pak2 cleavage protection) supports negative regulation of the extrinsic apoptotic pathway. Supporting Evidence: PMID:19240112 huntingtin exerts anti-apoptotic effects by binding to Pak2, which reduces the abilities of caspase-3 and caspase-8 to cleave Pak2 and convert it into a mediator of cell death.
GO:0005515 protein binding	IPI PMID:15654337 Polyglutamine expansion of huntingtin impairs its nuclear ex...	MARK AS OVER ANNOTATED	Summary: Generic protein binding reflecting the HTT-Tpr nuclear pore interaction. Captured better by HTT nuclear shuttling annotations. Reason: Generic protein binding; specific Tpr-mediated nuclear export relationship would warrant a more informative annotation if used.
GO:0005634 nucleus	IDA PMID:15654337 Polyglutamine expansion of huntingtin impairs its nuclear ex...	ACCEPT	Summary: N-terminal HTT shuttles between cytoplasm and nucleus and a nuclear pool of HTT exists. Accepted as the same general nuclear localization annotation already supported. Reason: Direct evidence of HTT nuclear localization and nucleocytoplasmic shuttling. Supporting Evidence: PMID:15654337 Here we report that N-terminal htt shuttles between the cytoplasm and nucleus in a Ran GTPase-independent manner.
GO:0005737 cytoplasm	IDA PMID:15654337 Polyglutamine expansion of huntingtin impairs its nuclear ex...	ACCEPT	Summary: Wild-type HTT is normally found in the cytoplasm. Accepted. Reason: Cytoplasmic localization is the dominant compartment for HTT. Supporting Evidence: PMID:15654337 wild-type htt, a 350-kDa protein of unknown function, is normally found in the cytoplasm.
GO:0005515 protein binding	IPI PMID:19498170 Rhes, a striatal specific protein, mediates mutant-huntingti...	MARK AS OVER ANNOTATED	Summary: Generic protein binding reflecting the Rhes/mHTT toxicity interaction. Disease-context interaction; not core HTT function. Reason: Generic protein binding from disease-context interaction.
GO:0048487 beta-tubulin binding	IDA PMID:11870213 Perinuclear localization of huntingtin as a consequence of i...	ACCEPT	Summary: HTT binds microtubules via beta-tubulin; this contributes to its perinuclear localization and microtubule-dependent trafficking. Direct molecular activity supported by biochemistry. Reason: Direct evidence for HTT-beta-tubulin interaction relevant to HTT's microtubule association.
GO:0005515 protein binding	IPI PMID:20515468 pARIS-htt: an optimised expression platform to study hunting...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from the pARIS-htt platform paper. The biologically informative annotations from this paper (dynein intermediate chain binding, vesicle transport along microtubule, retrograde Golgi-to-ER transport, Golgi organization, cytosol) are already separately present. Reason: Generic protein binding; specific functional annotations from the same paper exist.
GO:0005634 nucleus	IDA PMID:12783847 Huntingtin contains a highly conserved nuclear export signal...	ACCEPT	Summary: HTT contains a highly conserved nuclear export signal and a nuclear pool of HTT is recovered in nuclear fractions. Accepted nuclear localization. Reason: Conserved NES and demonstrated nuclear shuttling support a bona fide nuclear pool of HTT. Supporting Evidence: PMID:12783847 Huntingtin contains a highly conserved nuclear export signal.
GO:0005634 nucleus	IDA PMID:17704510 Huntingtin has a membrane association signal that can modula...	ACCEPT	Summary: HTT can translocate to the nucleus in response to ER stress; normal cytoplasmic localization is restored by the N17 membrane association signal. Accepted nuclear localization annotation. Reason: Direct evidence for stress-regulated nuclear translocation of HTT. Supporting Evidence: PMID:17704510 huntingtin has a normal biological function as an ER-associated protein that can translocate to the nucleus and back out in response to ER stress or other events.
GO:0005770 late endosome	IDA PMID:17704510 Huntingtin has a membrane association signal that can modula...	ACCEPT	Summary: HTT N17 directly targets the protein to late endosomes and autophagic vesicles. Core HTT localization for autophagy. Reason: Direct N17-mediated targeting of HTT to late endosomes established by mutagenesis and microscopy. Supporting Evidence: PMID:17704510 Huntingtin vesicular interaction mediated by 1-18 is specific to late endosomes and autophagic vesicles.
GO:0005776 autophagosome	IDA PMID:17704510 Huntingtin has a membrane association signal that can modula...	ACCEPT	Summary: HTT N17 specifically targets autophagic vesicles. Core HTT localization for autophagy scaffolding. Reason: Direct N17-mediated targeting of HTT to autophagic vesicles. Supporting Evidence: PMID:17704510 Huntingtin vesicular interaction mediated by 1-18 is specific to late endosomes and autophagic vesicles.
GO:0005783 endoplasmic reticulum	IDA PMID:17704510 Huntingtin has a membrane association signal that can modula...	ACCEPT	Summary: HTT N17 mediates ER association; HTT functions as an ER-associated protein that can shuttle to the nucleus under stress. Core HTT compartment. Reason: Direct evidence that the N17 amphipathic helix targets HTT to the ER. Supporting Evidence: PMID:17704510 The 18 amino-acid amino-terminus of huntingtin is an amphipathic alpha helical membrane-binding domain that can reversibly target to vesicles and the endoplasmic reticulum (ER).
GO:0006890 retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum	IMP PMID:20515468 pARIS-htt: an optimised expression platform to study hunting...	KEEP AS NON CORE	Summary: Loss of HTT functional domains in the pARIS-htt system affects retrograde Golgi-to-ER transport. Consistent with HTT's broader role in microtubule-dependent vesicle trafficking. Reason: Retrograde Golgi-to-ER transport is one specific subset of HTT-supported microtubule-based vesicle traffic; non-core relative to the general transport role.
GO:0032991 protein-containing complex	IDA PMID:18922795 Huntingtin regulates RE1-silencing transcription factor/neur...	MARK AS OVER ANNOTATED	Summary: HTT is part of a REST/NRSF-RILP-dynactin-HAP1 protein complex; the term is trivially true and uninformative on its own. Reason: Trivially true for any HTT context; uninformative.
GO:0034452 dynactin binding	IPI PMID:18922795 Huntingtin regulates RE1-silencing transcription factor/neur...	ACCEPT	Summary: HTT directly interacts with the dynactin p150Glued subunit; this is core to HTT's vesicle transport scaffold role coupling cargo to dynein/dynactin. Reason: Direct yeast two-hybrid and biochemical evidence for HTT binding to dynactin p150Glued. Supporting Evidence: PMID:18922795 Huntingtin did not interact directly with either REST/NRSF or RILP, but did interact with dynactin p150 Glued.
GO:0045505 dynein intermediate chain binding	IDA PMID:20515468 pARIS-htt: an optimised expression platform to study hunting...	ACCEPT	Summary: HTT binds the dynein intermediate chain (residues ~600-698 identified as DIC binding site by Caviston 2007); this is a core HTT molecular activity coupling cargo to retrograde microtubule transport. Reason: Yeast two-hybrid and affinity chromatography evidence for direct HTT-DIC interaction. Supporting Evidence: PMID:17548833 Htt and dynein intermediate chain interact directly; endogenous Htt and dynein co-immunoprecipitate from mouse brain cytosol.
GO:0047496 vesicle transport along microtubule	IMP PMID:20515468 pARIS-htt: an optimised expression platform to study hunting...	ACCEPT	Summary: Functional analysis of HTT domains in the pARIS-htt system confirms requirement for HTT in microtubule-dependent vesicle trafficking. Core HTT process. Reason: Direct demonstration that HTT functional domains are required for vesicle transport along microtubules. Supporting Evidence: PMID:17548833 Antibodies to Htt inhibited vesicular transport along microtubules, suggesting that Htt facilitates dynein-mediated vesicle motility.
GO:0005829 cytosol	IDA PMID:20515468 pARIS-htt: an optimised expression platform to study hunting...	ACCEPT	Summary: HTT shows cytosolic localization in the pARIS-htt system; consistent with the well-established cytoplasmic distribution. Reason: Cytosolic localization is well supported for HTT.
GO:0007030 Golgi organization	IMP PMID:20515468 pARIS-htt: an optimised expression platform to study hunting...	KEEP AS NON CORE	Summary: HTT RNAi causes Golgi disruption similar to dynein/dynactin compromise; HTT is required for proper Golgi organisation through its motor scaffold role. Kept as non-core because this is a downstream consequence of HTT's motor coupling. Reason: Golgi organisation is a downstream effect of HTT-dependent microtubule motor coupling, not an independent HTT activity. Supporting Evidence: PMID:17548833 Htt RNAi in HeLa cells results in Golgi disruption, similar to the effects of compromising dynein/dynactin function.
GO:0000132 establishment of mitotic spindle orientation	IMP PMID:20696378 Huntingtin is required for mitotic spindle orientation and m...	ACCEPT	Summary: HTT localises to spindle poles and is required for proper spindle orientation in cortical progenitors; loss mislocalises p150Glued/dynein/NuMA and disrupts spindle orientation. Core HTT process in dividing/neural progenitor cells. Reason: Direct in vitro and in vivo evidence that HTT controls mitotic spindle orientation via the dynactin/dynein/NuMA machinery. Supporting Evidence: PMID:20696378 RNAi-mediated silencing of huntingtin in cells disrupts spindle orientation by mislocalizing the p150(Glued) subunit of dynactin, dynein, and the large nuclear mitotic apparatus NuMA protein.
GO:0002039 p53 binding	IPI PMID:10823891 The Huntington's disease protein interacts with p53 and CREB...	KEEP AS NON CORE	Summary: HTT directly binds p53 and represses p53/CBP transcriptional activity. A specific functional interaction relevant to HTT's transcription-related scaffolding pool; kept as non-core given the dominance of trafficking/autophagy as HTT's main functions. Reason: p53 binding is a specific, supported HTT interaction but a non-core peripheral function relative to trafficking and autophagy. Supporting Evidence: PMID:10823891 The Huntington's disease protein interacts with p53 and CREB-binding protein and represses transcription.
GO:0005737 cytoplasm	IDA PMID:15064418 SUMO modification of Huntingtin and Huntington's disease pat...	ACCEPT	Summary: Cytoplasmic localization of HTT observed in SUMO modification study. Consistent with the dominant cytoplasmic compartment. Reason: Cytoplasmic localization of HTT is well established.
GO:0005737 cytoplasm	IDA PMID:7748555 Huntingtin is a cytoplasmic protein associated with vesicles...	ACCEPT	Summary: Duplicate cytoplasm annotation based on DiFiglia 1995 immunohistochemistry; the canonical reference for cytoplasmic HTT localization. Reason: Foundational direct evidence for HTT cytoplasmic localization. Supporting Evidence: PMID:7748555 Huntingtin is a cytoplasmic protein associated with vesicles in human and rat brain neurons.
GO:0030424 axon	IDA PMID:7748555 Huntingtin is a cytoplasmic protein associated with vesicles...	ACCEPT	Summary: Direct immunohistochemical evidence for HTT in cortical axonal compartments. Reason: Axonal localization of HTT is core to its vesicle-transport scaffold role. Supporting Evidence: PMID:7748555 Immunohistochemistry in human and rat brain revealed widespread cytoplasmic labeling of huntingtin within neurons, particularly cell bodies and dendrites
GO:0030425 dendrite	IDA PMID:7748555 Huntingtin is a cytoplasmic protein associated with vesicles...	ACCEPT	Summary: Direct immunohistochemical evidence for HTT in neuronal dendrites and cell bodies. Reason: Dendritic localization is well supported and consistent with HTT's neuronal vesicle scaffold role. Supporting Evidence: PMID:7748555 Immunohistochemistry in human and rat brain revealed widespread cytoplasmic labeling of huntingtin within neurons, particularly cell bodies and dendrites
GO:0030659 cytoplasmic vesicle membrane	IDA PMID:7748555 Huntingtin is a cytoplasmic protein associated with vesicles...	ACCEPT	Summary: HTT is associated with vesicle membranes as shown by ultrastructural analysis; consistent with its N17-mediated membrane targeting and Rab5/HAP40-mediated endosome recruitment. Reason: Direct ultrastructural evidence places HTT around vesicle membranes in cortical neurons. Supporting Evidence: PMID:7748555 At the ultrastructural level, immunoreactivity in cortical neurons was detected in the matrix of the cytoplasm and around the membranes of the vesicles.
GO:0005515 protein binding	IPI PMID:7477378 A huntingtin-associated protein enriched in brain with impli...	MARK AS OVER ANNOTATED	Summary: Generic protein binding reflecting the original HAP1 cloning paper (Li 1995). HAP1 is the founding HTT-associated protein and the interaction is core to HTT motor coupling, but the bare protein binding annotation is uninformative. Reason: Generic protein binding; the HAP1 interaction underpins HTT's motor scaffolding role which is captured by specific dynein/dynactin and microtubule-transport annotations.
GO:0005794 Golgi apparatus	IDA PMID:15837803 Optineurin links myosin VI to the Golgi complex and is invol...	ACCEPT	Summary: HTT colocalises with dynein at the Golgi in cell culture and HTT depletion disrupts Golgi organisation, supporting Golgi apparatus as a HTT-associated compartment via its motor scaffold role. Reason: Direct microscopy evidence for HTT at the Golgi consistent with its dynein-mediated vesicle trafficking role. Supporting Evidence: PMID:17548833 Both Htt and DIC are visible as puncta distributed throughout the cytoplasm with concentrations at the Golgi, consistent with partial colocalization.

Gene Description

Proposed New Ontology Terms

HTT N-terminal ubiquitin-binding domain — proposed annotation to GO:0043130 (ubiquitin binding)

Existing Annotations Review

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