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A Large Scale Huntingtin Protein Interaction Network Implicates Rho GTPase Signaling Pathways in Huntington Disease*

  • Cendrine Tourette
    Affiliations
    Buck Institute for Research on Aging, Novato, California 94945
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  • Biao Li
    Affiliations
    Buck Institute for Research on Aging, Novato, California 94945
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  • Russell Bell
    Affiliations
    Prolexys Pharmaceuticals, Salt Lake City, Utah 84116

    Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112
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  • Shannon O'Hare
    Affiliations
    Buck Institute for Research on Aging, Novato, California 94945
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  • Linda S. Kaltenbach
    Affiliations
    Prolexys Pharmaceuticals, Salt Lake City, Utah 84116

    Center for Drug Discovery and Department of Neurobiology, Duke University Medical Center, Durham, North Carolina 27704
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  • Sean D. Mooney
    Correspondence
    To whom correspondence may be addressed: The Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA 94945. Tel.: 415-209-2038; Fax: 415-493-3640;
    Affiliations
    Buck Institute for Research on Aging, Novato, California 94945
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  • Robert E. Hughes
    Correspondence
    To whom correspondence may be addressed: The Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA 94945. Tel.: 415-209-2069; Fax: 415-209-2235;
    Affiliations
    Buck Institute for Research on Aging, Novato, California 94945
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  • Author Footnotes
    * This work was supported, in whole or in part, by National Institutes of Health Grants NS055247 and GM084432 (to R. E. H.). This work was also supported by a grant from CHDI Foundation Inc. (to R. E. H.).
    ♦ This article was selected as a Paper of the Week.
    This article contains supplemental Tables S1–S5.
    3 The abbreviations used are:HDHuntington diseaseHIPhuntingtin-interacting proteinHPRDHuman Protein Resource DatabaseIPAingenuity pathway analysisY2Hyeast two-hybridHDNethuntingtin protein interaction networkPRRproline-rich regionSHSrc homologyBARBin-Amphiphysin-RvsPPIprotein-protein interactionILKintegrin-linked kinaseRARretinoic acid receptor.
Open AccessPublished:January 09, 2014DOI:https://doi.org/10.1074/jbc.M113.523696
      Huntington disease (HD) is an inherited neurodegenerative disease caused by a CAG expansion in the HTT gene. Using yeast two-hybrid methods, we identified a large set of proteins that interact with huntingtin (HTT)-interacting proteins. This network, composed of HTT-interacting proteins (HIPs) and proteins interacting with these primary nodes, contains 3235 interactions among 2141 highly interconnected proteins. Analysis of functional annotations of these proteins indicates that primary and secondary HIPs are enriched in pathways implicated in HD, including mammalian target of rapamycin, Rho GTPase signaling, and oxidative stress response. To validate roles for HIPs in mutant HTT toxicity, we show that the Rho GTPase signaling components, BAIAP2, EZR, PIK3R1, PAK2, and RAC1, are modifiers of mutant HTT toxicity. We also demonstrate that Htt co-localizes with BAIAP2 in filopodia and that mutant HTT interferes with filopodial dynamics. These data indicate that HTT is involved directly in membrane dynamics, cell attachment, and motility. Furthermore, they implicate dysregulation in these pathways as pathological mechanisms in HD.

      Introduction

      Huntington disease is an autosomal dominant neurodegenerative disease caused by a CAG repeat expansion in the first exon of the HTT gene that encodes the protein huntingtin (HTT) (
      • The Huntington's Disease Collaborative Research Group
      A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes.
      ). HD
      The abbreviations used are:
      HD
      Huntington disease
      HIP
      huntingtin-interacting protein
      HPRD
      Human Protein Resource Database
      IPA
      ingenuity pathway analysis
      Y2H
      yeast two-hybrid
      HDNet
      huntingtin protein interaction network
      PRR
      proline-rich region
      SH
      Src homology
      BAR
      Bin-Amphiphysin-Rvs
      PPI
      protein-protein interaction
      ILK
      integrin-linked kinase
      RAR
      retinoic acid receptor.
      manifests with progressive motor and psychiatric impairments caused by neuronal dysfunction and loss in the cortex and striatum (
      • Reiner A.
      • Albin R.L.
      • Anderson K.D.
      • D'Amato C.J.
      • Penney J.B.
      • Young A.B.
      Differential loss of striatal projection neurons in Huntington disease.
      ,
      • Walker F.O.
      Huntington's disease.
      ). Huntingtin is involved in a variety of cellular functions, including vesicle transport, transcription, and energy metabolism (
      • Borrell-Pagès M.
      • Zala D.
      • Humbert S.
      • Saudou F.
      Huntington's disease: from huntingtin function and dysfunction to therapeutic strategies.
      ). HD pathogenesis is generally thought to result from a combination of a gain of toxic properties by mutant HTT as well as a loss of normal huntingtin function (
      • Zuccato C.
      • Valenza M.
      • Cattaneo E.
      Molecular mechanisms and potential therapeutical targets in Huntington's disease.
      ). Huntingtin is an ∼350-kDa protein containing a polyglutamine (polyQ) region, a proline-rich region (PRR), HEAT (Huntingtin, elongation factor 3, protein phosphatase 2A, target of rapamycin 1) repeats, and a number of caspase cleavage sites (
      • Borrell-Pagès M.
      • Zala D.
      • Humbert S.
      • Saudou F.
      Huntington's disease: from huntingtin function and dysfunction to therapeutic strategies.
      ,
      • Wellington C.L.
      • Ellerby L.M.
      • Gutekunst C.A.
      • Rogers D.
      • Warby S.
      • Graham R.K.
      • Loubser O.
      • van Raamsdonk J.
      • Singaraja R.
      • Yang Y.Z.
      • Gafni J.
      • Bredesen D.
      • Hersch S.M.
      • Leavitt B.R.
      • Roy S.
      • Nicholson D.W.
      • Hayden M.R.
      Caspase cleavage of mutant huntingtin precedes neurodegeneration in Huntington's disease.
      ). Several studies have emphasized a critical role of misfolded N-terminal fragments of mutant HTT (
      • Graham R.K.
      • Deng Y.
      • Slow E.J.
      • Haigh B.
      • Bissada N.
      • Lu G.
      • Pearson J.
      • Shehadeh J.
      • Bertram L.
      • Murphy Z.
      • Warby S.C.
      • Doty C.N.
      • Roy S.
      • Wellington C.L.
      • Leavitt B.R.
      • Raymond L.A.
      • Nicholson D.W.
      • Hayden M.R.
      Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin.
      ,
      • Ratovitski T.
      • Gucek M.
      • Jiang H.
      • Chighladze E.
      • Waldron E.
      • D'Ambola J.
      • Hou Z.
      • Liang Y.
      • Poirier M.A.
      • Hirschhorn R.R.
      • Graham R.
      • Hayden M.R.
      • Cole R.N.
      • Ross C.A.
      Mutant huntingtin N-terminal fragments of specific size mediate aggregation and toxicity in neuronal cells.
      ) that are natural products of HTT processing (
      • Sun B.
      • Fan W.
      • Balciunas A.
      • Cooper J.K.
      • Bitan G.
      • Steavenson S.
      • Denis P.E.
      • Young Y.
      • Adler B.
      • Daugherty L.
      • Manoukian R.
      • Elliott G.
      • Shen W.
      • Talvenheimo J.
      • Teplow D.B.
      • Haniu M.
      • Haldankar R.
      • Wypych J.
      • Ross C.A.
      • Citron M.
      • Richards W.G.
      Polyglutamine repeat length-dependent proteolysis of huntingtin.
      ). HTT is known to have a large number of interacting proteins involved in a diverse range of biological processes. Numerous studies have shown that polyQ expansion in HTT may alter biological processes that are essential for cellular homeostasis and neuronal survival through impairment of its protein binding activities (
      • Boutell J.M.
      • Thomas P.
      • Neal J.W.
      • Weston V.J.
      • Duce J.
      • Harper P.S.
      • Jones A.L.
      Aberrant interactions of transcriptional repressor proteins with the Huntington's disease gene product, huntingtin.
      ,
      • Holbert S.
      • Denghien I.
      • Kiechle T.
      • Rosenblatt A.
      • Wellington C.
      • Hayden M.R.
      • Margolis R.L.
      • Ross C.A.
      • Dausset J.
      • Ferrante R.J.
      • Néri C.
      The Gln-Ala repeat transcriptional activator CA150 interacts with huntingtin: neuropathologic and genetic evidence for a role in Huntington's disease pathogenesis.
      ,
      • Steffan J.S.
      • Kazantsev A.
      • Spasic-Boskovic O.
      • Greenwald M.
      • Zhu Y.Z.
      • Gohler H.
      • Wanker E.E.
      • Bates G.P.
      • Housman D.E.
      • Thompson L.M.
      The Huntington's disease protein interacts with p53 and CREB-binding protein and represses transcription.
      ,
      • Caviston J.P.
      • Ross J.L.
      • Antony S.M.
      • Tokito M.
      • Holzbaur E.L.
      Huntingtin facilitates dynein/dynactin-mediated vesicle transport.
      ).
      A number of large scale screens aimed to elucidate new pathways involved in HD pathogenesis by defining HTT partners using yeast two-hybrid (Y2H) and affinity purification approaches (
      • Culver B.P.
      • Savas J.N.
      • Park S.K.
      • Choi J.H.
      • Zheng S.
      • Zeitlin S.O.
      • Yates 3rd, J.R.
      • Tanese N.
      Proteomic analysis of wild-type and mutant huntingtin-associated proteins in mouse brains identifies unique interactions and involvement in protein synthesis.
      ,
      • Goehler H.
      • Lalowski M.
      • Stelzl U.
      • Waelter S.
      • Stroedicke M.
      • Worm U.
      • Droege A.
      • Lindenberg K.S.
      • Knoblich M.
      • Haenig C.
      • Herbst M.
      • Suopanki J.
      • Scherzinger E.
      • Abraham C.
      • Bauer B.
      • Hasenbank R.
      • Fritzsche A.
      • Ludewig A.H.
      • Büssow K.
      • Buessow K.
      • Coleman S.H.
      • Gutekunst C.A.
      • Landwehrmeyer B.G.
      • Lehrach H.
      • Wanker E.E.
      A protein interaction network links GIT1, an enhancer of huntingtin aggregation, to Huntington's disease.
      ,
      • Kaltenbach L.S.
      • Romero E.
      • Becklin R.R.
      • Chettier R.
      • Bell R.
      • Phansalkar A.
      • Strand A.
      • Torcassi C.
      • Savage J.
      • Hurlburt A.
      • Cha G.H.
      • Ukani L.
      • Chepanoske C.L.
      • Zhen Y.
      • Sahasrabudhe S.
      • Olson J.
      • Kurschner C.
      • Ellerby L.M.
      • Peltier J.M.
      • Botas J.
      • Hughes R.E.
      Huntingtin interacting proteins are genetic modifiers of neurodegeneration.
      ,
      • Shirasaki D.I.
      • Greiner E.R.
      • Al-Ramahi I.
      • Gray M.
      • Boontheung P.
      • Geschwind D.H.
      • Botas J.
      • Coppola G.
      • Horvath S.
      • Loo J.A.
      • Yang X.W.
      Network organization of the huntingtin proteomic interactome in mammalian brain.
      ). Analyses of binary interactions or complexes identify the first level of HTT-interacting proteins. We have previously described a protein interaction network derived from a comprehensive Y2H screen using HTT as a bait. That study reported 102 high confidence HTT-interacting proteins, and many of these were shown to be modifiers of mutant HTT toxicity in a Drosophila model of HD (
      • Kaltenbach L.S.
      • Romero E.
      • Becklin R.R.
      • Chettier R.
      • Bell R.
      • Phansalkar A.
      • Strand A.
      • Torcassi C.
      • Savage J.
      • Hurlburt A.
      • Cha G.H.
      • Ukani L.
      • Chepanoske C.L.
      • Zhen Y.
      • Sahasrabudhe S.
      • Olson J.
      • Kurschner C.
      • Ellerby L.M.
      • Peltier J.M.
      • Botas J.
      • Hughes R.E.
      Huntingtin interacting proteins are genetic modifiers of neurodegeneration.
      ). In this study, we report Y2H screening results for these primary HTT-interacting partners derived from a genome-scale interaction map (
      • Bell R.
      • Hubbard A.
      • Chettier R.
      • Chen D.
      • Miller J.P.
      • Kapahi P.
      • Tarnopolsky M.
      • Sahasrabuhde S.
      • Melov S.
      • Hughes R.E.
      A human protein interaction network shows conservation of aging processes between human and invertebrate species.
      ,
      • Bandyopadhyay S.
      • Chiang C.Y.
      • Srivastava J.
      • Gersten M.
      • White S.
      • Bell R.
      • Kurschner C.
      • Martin C.
      • Smoot M.
      • Sahasrabudhe S.
      • Barber D.L.
      • Chanda S.K.
      • Ideker T.
      A human MAP kinase interactome.
      ). Using the 102 HTT primary partners identified in our first screen, we identified a secondary interactome of 2038 known partners to build an expanded huntingtin protein interaction network (HDNet). This network includes HTT-primary, primary-primary, and primary-secondary interacting proteins. We analyzed the connectivity properties of these proteins at the two levels, showing significantly high interconnectivity between HDNet members compared with random proteins in a global curated interaction network from Human Protein Resource Database (HPRD).
      Integration of data from different “omics” approaches has been shown to improve functional annotations and to help to formulate biological hypotheses (
      • Ge H.
      • Walhout A.J.
      • Vidal M.
      Integrating ‘omic’ information: a bridge between genomics and systems biology.
      ). Combination of biological annotations with integration of gene expression data from post-mortem HD brain highlighted the role of Rho family GTPase signaling proteins in HD pathology. Using cell models, we showed that components of this pathway are modifiers of expanded polyQ-induced toxicity. We also showed that mutant HTT interferes with BAIAP2-induced filopodia formation, validating the role of Rho signaling in mutant HTT toxicity. Our study provides a comprehensive resource of binary protein interactions that define novel pathways contributing to Huntington disease pathology.

      DISCUSSION

      Here, we describe HDNet, a protein interaction network that provides a genome-scale resource for elucidating normal functions of HTT, novel pathogenic mechanisms of mutant HTT, as well as deeper mechanistic insights into known pathways affected in HD. Partners of HTT identified in our screen, at both primary and secondary levels of interaction, showed enhanced interconnectivity as compared with other proteins in the context of HPRD, an independently derived and curated reference protein interaction network. We demonstrated that this connectivity is not due to node degree effects or annotation biases in HPRD. We conclude that independent validation of enhanced connectivity of HDNet arises from shared functional properties relevant to the functions of HTT as well as the pathogenic process in Huntington disease.
      HDNet is significantly enriched in proteins that function in pathways known to be involved in HD, such as protein homeostasis, cytoskeleton, and vesicle trafficking (Fig. 3). These pathways were recently discovered and described as preferentially enriched in HTT partners from two interaction screens by affinity purification followed by mass spectrometry from brain of HD mouse models (
      • Culver B.P.
      • Savas J.N.
      • Park S.K.
      • Choi J.H.
      • Zheng S.
      • Zeitlin S.O.
      • Yates 3rd, J.R.
      • Tanese N.
      Proteomic analysis of wild-type and mutant huntingtin-associated proteins in mouse brains identifies unique interactions and involvement in protein synthesis.
      ,
      • Shirasaki D.I.
      • Greiner E.R.
      • Al-Ramahi I.
      • Gray M.
      • Boontheung P.
      • Geschwind D.H.
      • Botas J.
      • Coppola G.
      • Horvath S.
      • Loo J.A.
      • Yang X.W.
      Network organization of the huntingtin proteomic interactome in mammalian brain.
      ). Here, we demonstrate that expanding the HD network with secondary interacting partners and combining enriched functional modules with gene expression dysregulation data from human brain tissue highlights signaling by Rho family GTPases and actin remodeling as being processes in HTT function and HD pathogenesis.
      HDNet is a protein interaction network defined at the protein domain resolution. Identification of binding domain underlying protein interaction networks enhances our mechanistic understanding of how normal and pathological mechanisms may operate at the molecular level (
      • Ngounou Wetie A.G.
      • Sokolowska I.
      • Woods A.G.
      • Roy U.
      • Deinhardt K.
      • Darie C.C.
      Protein-protein interactions: switch from classical methods to proteomics and bioinformatics-based approaches.
      ). This study used a Y2H method based on construction of binding domain and activation domain libraries from cDNA fragments. Therefore, interactions reported here are between protein fragments rather than between full-length proteins (
      • Kaltenbach L.S.
      • Romero E.
      • Becklin R.R.
      • Chettier R.
      • Bell R.
      • Phansalkar A.
      • Strand A.
      • Torcassi C.
      • Savage J.
      • Hurlburt A.
      • Cha G.H.
      • Ukani L.
      • Chepanoske C.L.
      • Zhen Y.
      • Sahasrabudhe S.
      • Olson J.
      • Kurschner C.
      • Ellerby L.M.
      • Peltier J.M.
      • Botas J.
      • Hughes R.E.
      Huntingtin interacting proteins are genetic modifiers of neurodegeneration.
      ,
      • LaCount D.J.
      • Vignali M.
      • Chettier R.
      • Phansalkar A.
      • Bell R.
      • Hesselberth J.R.
      • Schoenfeld L.W.
      • Ota I.
      • Sahasrabudhe S.
      • Kurschner C.
      • Fields S.
      • Hughes R.E.
      A protein interaction network of the malaria parasite Plasmodium falciparum.
      ). In many cases these fragments were shown to contain specific conserved protein domains (as defined by the NCBI conserved domain database). Knowledge of specific domain-domain interactions provides a higher resolution understanding of how specific proteins are interacting with HTT itself as well as HTT binding partners. With regard to HD pathogenesis, identification of binding domains of HTT partners is of high interest. Some studies suggest that the normal role of polyQ regions in proteins would be to stabilize PPI, and expansion of polyQ could have a deleterious effect through a gain of abnormal interactions or impairments of protein interaction dynamics (
      • Schaefer M.H.
      • Wanker E.E.
      • Andrade-Navarro M.A.
      Evolution and function of CAG/polyglutamine repeats in protein-protein interaction networks.
      ). Recently, the role of the proline-rich region of HTT has been highlighted in different studies. Intrabodies targeting PRR were shown to reduce toxicity of mutant HTT and increase turnover of mutant HTT (
      • Southwell A.L.
      • Khoshnan A.
      • Dunn D.E.
      • Bugg C.W.
      • Lo D.C.
      • Patterson P.H.
      Intrabodies binding the proline-rich domains of mutant huntingtin increase its turnover and reduce neurotoxicity.
      ). It was also shown that deletion of the PRR domain in full-length HTT caused late onset learning and memory deficits in transgenic mice (
      • Neveklovska M.
      • Clabough E.B.
      • Steffan J.S.
      • Zeitlin S.O.
      Deletion of the huntingtin proline-rich region does not significantly affect normal huntingtin function in mice.
      ). This suggests that protein interaction with the PRR domain of HTT can affect both its normal and toxic activities as well as turnover. Partners of HTT containing SH3 or WW domains in the binding sequences could thus represent an interesting group of modifiers. We also note that a number of proteins with SH3 domains are involved in cell motility pathways. These are SRGAP1, SRGAP2, SRGAP3, and BAIAP2.
      Based on analysis of canonical pathways represented in HDNet and gene expression changes observed in HD brain, we focused on RhoGTPase signaling to validate a specific functional module as being involved in HTT function and toxicity. The potent loss-of-function suppression of HTT toxicity observed in STHdh111Q/111Q cells upon knockdown of BAIAP2 further focused our attention on filopodia components as modifiers of mutant HTT toxicity in cell models. These structures are essential for cell adhesion, cell migration, and neurite outgrowth (
      • Ahmed S.
      • Goh W.I.
      • Bu W.
      I-BAR domains, IRSp53 and filopodium formation.
      ). Here, we show that expression of mutant HTT impairs BAIAP2-induced filopodia formation. This phenomenon is observed for induction of filopodia formation following BAIAP2 overexpression, as well as a decrease of formation of these structures following knockdown of BAIAP2. This suggests that mutant HTT can impair dynamic regulation of filopodia by BAIAP2. The regulation of BAIAP2-induced filopodial formation remains to be elucidated, as well as the specific involvement of this process in neuron-specific pathways. BAIAP2 is also a binding partner of PDZ domain-containing proteins such as DGL-4 (PSD-95) in the postsynaptic density indicating that the HTT-BAIAP2 interaction may influence both pre- and post-synaptic processes (
      • Hori K.
      • Yasuda H.
      • Konno D.
      • Maruoka H.
      • Tsumoto T.
      • Sobue K.
      NMDA receptor-dependent synaptic translocation of insulin receptor substrate p53 via protein kinase C signaling.
      ,
      • Soltau M.
      • Berhörster K.
      • Kindler S.
      • Buck F.
      • Richter D.
      • Kreienkamp H.J.
      Insulin receptor substrate of 53 kDa links postsynaptic shank to PSD-95.
      ). BAIAP2 has also has been shown to interact with ATN1 (atrophin-1), the protein responsible for DRPLA, a polyQ expansion disease with pathological and clinical similarities to HD (
      • Thomas E.A.
      • Foye P.E.
      • Alvarez C.E.
      • Usui H.
      • Sutcliffe J.G.
      Insulin receptor substrate protein p53 localization in rats suggests mechanism for specific polyglutamine neurodegeneration.
      ). Identifying the protein composition of filopodia neurons affected in HD, and deciphering the involvement of HTT in these dynamic structures could help elucidate novel mechanisms of neuronal dysfunction. In human brain, previous studies showed marked morphological changes in dendritic structures and branching of medium spiny neurons in post-mortem HD brain (
      • Ferrante R.J.
      • Kowall N.W.
      • Richardson Jr., E.P.
      Proliferative and degenerative changes in striatal spiny neurons in Huntington's disease: a combined study using the section-Golgi method and calbindin D28k immunocytochemistry.
      ,
      • Graveland G.A.
      • Williams R.S.
      • DiFiglia M.
      Evidence for degenerative and regenerative changes in neostriatal spiny neurons in Huntington's disease.
      ). Our data indicate that dynamic organization of neuronal processes as well as sites of cell-cell contacts may be a primary pathogenic mechanism in HD. Furthermore, we provide evidence that components of the Rho GTPase signaling cascade such as BAIAP2 can be directly affected by mutant HTT and are therefore candidates for HTT-mediated defects in cell morphology. The protein machinery regulating cytoskeleton-membrane interactions and filopodia formation represents key targets for further studies with regard to neurodevelopmental pathways and synaptic homeostasis in Huntington disease.

      Author Profile

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