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FLASH GENE
Symbol HTT contributors: mct/pgu/shn - updated : 03-06-2019
HGNC name huntingtin
HGNC id 4851
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • N-terminal 17 AAs domain, sequence highly conserved across species, having properties of a cytosolic retention signal, required for mitochondrial association, playing a key role in regulating its toxicity and aggregation, and acting as a nuclear export sequence (NES) within HTT exon , associated to a KPNB2-dependent proline-tyrosine (PY)-NLS
  • a stretch of glutamine encoded by CCG repeat and CAG repeat
  • ten HEAT repeats
  • five pentapeptide motif (LxxLL) not necessary for the huntingtin-NR1H3 interaction or for activation of NR1H3 mediated transcription
  • the first 17 AAs, the proline-rich sequence C-terminal with an expanded polyQ peptide decreases aggregate, influencing sub-cellular localization, protein stability, binding to the SH3 domain of DLG4 (
    • secondary structure a large hinged {alpha}-helical solenoid, which serves as a facilitator of the PRC2 complex, now provides a nuanced view of the molecule and its polymorphic polyglutamine region
    HOMOLOGY
    interspecies ortholog to Htt, Mus musculus
    ortholog to Htt, Rattus norvegicus
    ortholog to htt, danio rerio
    ortholog to HTT, Pan troglodyts
    Homologene
    FAMILY
  • hungtintin family
    • CATEGORY transport
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,mitochondria
    intracellular,cytoplasm,organelle,endoplasmic reticulum
    intracellular,cytoplasm,organelle,Golgi
    intracellular,cytoplasm,organelle,endosome
    intracellular,cytoplasm,organelle,lysosome
    intracellular,cytoplasm,cytosolic,vesicle
    intracellular,cytoplasm,cytoskeleton,microtubule
    intracellular,nucleus,nucleoplasm,nuclear bodies,nuclear speckles
    intracellular,nucleus,nucleolus
    text
  • distinct subsets of cytoplasmic and nuclear organelles
  • N-terminus shuttles between the cytoplasm and nucleus in an Ran-GTPase- independent manner
  • clathrin-coated and non-coated vesicles
  • perinuclear subcellular localization with a potential role in trafficking a discrete set of proteins between the Golgi and the extracellular space
  • in the HD brain, localized mainly in the cytoplasm; however, a small portion of mutant HTT localizes in subcellular organelles, including the plasma membrane, mitochondria, lysosomes and endoplasmic reticulum
  • found both in the nucleus and in the cytoplasm where it associates with a variety of organelles, including endoplasmic reticulum, Golgi apparatus, and mitochondria
  • primarily a cytoplasmic protein, known to be both vesicle- and microtubule-associated
  • association of HTT to the ER membrane is mediated by the first 18 amino acids, and this association is affected by ER stress (
    • basic FUNCTION
  • involved in intracellular organelle or axonal transport and in the organization of the centrosome
  • interacting with CREBBP and TP53 for transcription repression
  • iron Fe2+ regulated protein essential for normal nuclear and perinuclear organelles
  • involved in RNA biogenesis and cellular trafficking by control of UPP (ubiquitin proteasome pathway)
  • stimulating endosomal-lysosomal activity and autophagic process of cell death
  • playing a role in the regulation of microtubule-mediated transport or vesicle function (particularly BDNF transport)
  • acting in the cytoplasm of neurons to regulate the availability of REST to its nuclear NRSE-binding site
  • playing an integral role in mitochondrial energy metabolism (polyglutamine tract appears to regulate mitochondrial ADP-phosphorylation in a Ca(2+)-dependent process )
  • playing a role in MAPK pathway, in the ERK and JNK activation
  • playing a role in the intracellular trafficking of proteins required for the construction of the extracellular matrix
  • involved in NF-Y sequesteration leading to the reduction of HSPA4 gene expression
  • may be a component of a P body and functions in post-transcriptional repression pathways
  • being a positive regulatory factor for vesicular transport (promoting anterograde transport, when phosphorylated)
  • required for the generation and expansion of hematopoietic cells (
  • implicated in numerous cellular processes such as transcriptional regulation, mitochondria energetics, structural scaffolding, vesicle trafficking, endocytosis, and dentrite formation
  • positive regulatory factor for vesicular transport whose function is lost in disease
  • role in the regulation of cerebral spinal fluid (CSF) homeostasis (
  • 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
  • regulates the assembly of the dynein–dynactin complex for axonal transport and Golgi apparatus organization
  • may regulate expression of ABCG1 and CYP7A1 via multiple targets
  • with HAP1, participate in intracellular trafficking and polyglutamine expansion affects vesicular transport
  • may function to repress translation of mRNA during transport in neuronal granules
  • stimulates the transport of nuclear factor kappa light-chain-enhancer of activated B cells (NF-KB) out of dendritic spines (where NF-KB is activated by excitatory synaptic input) (
  • may play potentially a role similar to that of importin-beta1 in the retrograde transport of nuclear localization signal-containing cargoes from synapses toward the nucleus (
  • could participate in the distribution of the dynein–dynactin complex at the cell cortex and, as a consequence, regulate mitosis at several points
  • regulates cortical neurogenesis through, at least in part, its role during spindle pole orientation
  • role in the dynein-mediated intracellular trafficking of endosomes and lysosomes (
  • important biochemical function for HTT modulation of ZDHHC17 palmitoylation and its enzymatic activity
  • in addition to serving as a palmitoylation substrate, wild-type HTT also modulates the palmitoylation of ZDHHC17 itself
  • is required for multiple stages of neural induction, whereas mutant HTT enhances this process and promotes precocious neurogenesis and oligodendrocyte progenitor cell elaboration
  • HTT and HAP1 are regulators of autophagosome transport in neurons, suggesting that misregulation of autophagosome transport in Huntington disease leads to inefficient autophagosome maturation, potentially due to inhibition of autophagosome/lysosome fusion along the axon
  • is involved directly in membrane dynamics, cell attachment, and motility
  • is necessary for mitochondrial structure and function from the earliest stages of embryogenesis
  • is a component of the pathway regulating the orientation of mammary stem cell division, with potential implications for their self-renewal and differentiation properties
  • cortical HTT is required for the correct establishment of cortical and striatal excitatory circuits, and this function of HTT is lost when the mutant HTT is present
  • functions as a scaffold protein for selective macroautophagy but it is dispensable for non-selective macroautophagy
  • important for ciliogenesis and potentially implicated in autosomal dominant polycystic kidney disease (ADPKD)
    • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS cellular trafficking transport
    PATHWAY
    metabolism
    signaling
    a component
  • REST, DCTN1, HTT, HAP1, and RILP form a complex involved in the translocation of REST into the nucleus and HAP1 controls REST cellular localization in neurons
    • INTERACTION
    DNA
    RNA
    small molecule microtubule motors AND actin-associated adaptor molecules
    protein
  • microtubular calmodulin, EGFR, CBS, and TGM2
  • GAPDH, HAP1, HIP1 and HIP2
  • TPR
  • SP1 and TAF4
  • components of the NF-Y transcriptional factor (NFYA) (mutant form)
  • EIF2C2 (localization to P bodies provides evidence connecting HTT with the post-transcriptional control of gene expression and P body integrity)
  • human ubiquitin-conjugating enzyme, hE2-25K (
  • Grb2, RasGAP, and tyrosine-phosphorylated EGF receptoR (
  • cystathionine beta-synthase, CBS (
  • huntingtin-associated protein, HAP1 (
  • HYPA, HYPB, HYPC spliceosome proteins (
  • SH3-domain GRB2-like 3, SH3GL3 (
  • nuclear receptor co-repressor, N-CoR (
  • mixed-lineage kinase 2, MLK2 (
  • p53 and CREB-binding protein (
  • 40-kDa Huntingtin-associated protein, HAP40 (
  • Huntingtin-interacting protein I, HIP1 (
  • carboxy-terminal region of FIP-2 (
  • associated with N-methyl-d-aspartate (NMDA) and kainate receptors via postsynaptic density 95 (
  • transcriptional corepressor C-terminal binding protein, CtBP (
  • transcriptional activator Sp1 (
  • beta-tubulin (
  • serine/threonine protein kinase Akt (
  • protein kinase C and casein kinase substrate in neurons 1, PACSIN1 (
  • Huntingtin-interacting protein 14, HIP14 (
  • Cdc42-interacting protein 4, CIP4 (
  • repressor element-1 transcription factor, REST/neuron restrictive silencer element, NRSE (
  • caspase-2, CASP2 (
  • toxic huntingtin interacts with the benign polyQ repeat of TATA box binding protein (
  • Mutant huntingtin bound much stronger to CREB binding protein (
  • link between RAB5A, F8A1, and HTT, suggesting mechanism regulating cytoskeleton-dependent endosome dynamics and its dysfunction under pathological conditions
  • PFN1 interacts with HTT, as being a direct target of the ROCK1 isoform
  • Argonaute, AGO2 (
  • co-factor of NR1H3 (activity is lost by mutant huntingtin that only interacts weakly with NR1H3)
  • nuclear factor kappa light-chain-enhancer of activated B cells NF-KB that has been recently implicated in neural-specific functions
  • cytosplasmic dynein, a motor protein that drives cargoes along microtubular tracks toward the minus end
  • regulates spindle orientation by ensuring the proper localization of the DCTN1 subunit of dynactin, dynein and NUMA1
  • TRAF6 interacts with and ubiquitinates WT and mutant HTT
  • may also function as an allosteric activator of ZDHHC17
  • HTT regulates ciliogenesis by interacting through HAP1 with pericentriolar material 1 protein (PCM1)
  • CALB2 is preferentially associated with mutant HTT, although it also interacts with wild-type HTT
  • SRSF6 splicing factor binds to the 5prime end of the HTT gene with an expanded CAG repeat, consistent with its known recognition motif
  • may be a co-factor with mutant huntingtin in cell death
  • HTT-MECP2 interactions are enhanced in the presence of the expanded polyglutamine (polyQ) tract and are stronger in the nucleus compared with the cytoplasm
  • serine/threonine kinase AKT1, which regulates HTT function, rescued the spindle misorientation caused by the mutant HTT, by serine 421 (S421) phosphorylation
    • cell & other
    REGULATION
    activated by upregulation of transcription of brain derived neurotrophic factor (necessary for survival of striatal neurons)
    Other phosphorylated on S421 by the kinase Akt (protective effect against the toxicity of polyglutamine-expansion showing a regional distribution with the highest levels in the cerebellum, less in the cortex, and least in the striatum) (being crucial to control the direction of vesicles in neurons)
    can be cleaved by caspases and calpains at multiple sites within the region between AAs 460 and 600 (14, 19-29); cleavage at position 586 by caspase 6 is of particular importance for HD pathogenesis
    HTT is palmitoylated by ZDHHC17 and 13
    ASSOCIATED DISORDERS
    corresponding disease(s) HD
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional       gain of function
    a toxic gain of function of the mutant huntingtin
    Susceptibility
    Variant & Polymorphism
    Candidate gene calcium and mitochondrial permeability transition pore blockers may have a therapeutic potential for treatment of HD
    Marker
    Therapy target
    ANIMAL & CELL MODELS
  • Homozygotes mice for disruption of exon 5 of the Htt gene (Hdhex5) die before embryonic day 8.5, initiate gastrulation, but do not proceed to the formation of somites or to organogenesis. Mice heterozygous for the Hdhex5 mutation display increased motor activity and cognitive deficits with significant neuronal loss in the subthalamic nucleus
  • adult mice with a precise deletion of the short CAG triplet repeat encoding 7Q in the mouse HD gene commit more errors initially in the Barnes circular maze learning and memory test (
  • conditional inactivation of the Hdh mouse gene in Wnt1 cell lineages results in congenital hydrocephalus (
  • huntingtin loss-of-function on the developing nervous system of zebrafish causes distinct defects in morphology of neuromasts, olfactory placode and branchial arches (
  • mice expressing mutant htt, resistant to cleavage by caspase-6 but not caspase-3, maintain normal neuronal function and do not develop striatal neurodegeneration
  • Meclizine is neuroprotective in models of Huntington's disease