CHIP is an E3-ubiquitin ligase that contributes to healthy aging and has been characterized as neuroprotective. To elucidate dominant CHIP-dependent changes in protein steady-state levels in a patient-derived human neuronal model, CHIP function was ablated using gene-editing and an unbiased proteomic analysis conducted to compare knock-out and wild-type isogenic induced pluripotent stem cell (iPSC)-derived cortical neurons. Rather than a broad effect on protein homeostasis, loss of CHIP function impacted on a focused cohort of proteins from actin cytoskeleton signaling and membrane integrity networks. In support of the proteomics, CHIP knockout cells had enhanced sensitivity to induced membrane damage. We conclude that the major readout of CHIP function in cortical neurons derived from iPSC of a patient with elevate α-synuclein, Parkinson's disease and dementia, is the modulation of substrates involved in maintaining cellular "health". Thus, regulation of the actin cytoskeletal and membrane integrity likely contributes to the neuroprotective function(s) of CHIP.

Centre for Regenerative Medicine Institute for Stem Cell Research School of Biological Sciences The University of Edinburgh Edinburgh EH16 4UU UK

Institute of Genetics and Cancer University of Edinburgh Edinburgh EH4 2XU UK

Membrane Integrity Group Danish Cancer Society Research Center Strandboulevarden 49 2100 Copenhagen Denmark

Research Centre for Applied Molecular Oncology Masaryk Memorial Cancer Institute 656 53 Brno Czech Republic

University of Gdansk International Centre for Cancer Vaccine Science 80 822 Gdansk Poland

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iScience. 2022 Feb 23;25(3):103921. doi: 10.1016/j.isci.2022.103921. PubMed

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Adachi H., Waza M., Tokui K., Katsuno M., Minamiyama M., Tanaka F., Doyu M., Sobue G. CHIP overexpression reduces mutant androgen receptor protein and ameliorates phenotypes of the spinal and bulbar muscular atrophy transgenic mouse model. J. Neurosci. 2007;27:5115–5126. PubMed PMC

Al-Ramahi I., Lam Y.C., Chen H.K., de Gouyon B., Zhang M., Pérez A.M., Branco J., de Haro M., Patterson C., Zoghbi H.Y. CHIP protects from the neurotoxicity of expanded and wild-type ataxin-1 and promotes their ubiquitination and degradation. J. Biol. Chem. 2006;281:26714–26724. PubMed

Alberti S., Demand J., Esser C., Emmerich N., Schild H., Hohfeld J. Ubiquitylation of BAG-1 suggests a novel regulatory mechanism during the sorting of chaperone substrates to the proteasome. J. Biol. Chem. 2002;277:45920–45927. PubMed

Arndt V., Dick N., Tawo R., Dreiseidler M., Wenzel D., Hesse M., Fürst D.O., Saftig P., Saint R., Fleischmann B.K. Chaperone-assisted selective autophagy is essential for muscle maintenance. Curr. Biol. 2010;20:143–148. PubMed

Baines A.J., Lu H.C., Bennett P.M. The Protein 4.1 family: hub proteins in animals for organizing membrane proteins. Biochim. Biophys. Acta. 2014;1838:605–619. PubMed

Ballinger C.A., Connell P., Wu Y., Hu Z., Thompson L.J., Yin L.Y., Patterson C. Identification of CHIP, a novel tetratricopeptide repeat-containing protein that interacts with heat shock proteins and negatively regulates chaperone functions. Mol. Cell Biol. 1999;19:4535–4545. PubMed PMC

Bamburg J.R., Bloom G.S. Cytoskeletal pathologies of Alzheimer disease. Cell Motil Cytoskeleton. 2009;66:635–649. PubMed PMC

Bezanilla M., Gladfelter A.S., Kovar D.R., Lee W.L. Cytoskeletal dynamics: a view from the membrane. J. Cell Biol. 2015;209:329–337. PubMed PMC

Bezprozvanny I., Hiesinger P.R. The synaptic maintenance problem: membrane recycling, Ca2+ homeostasis and late onset degeneration. Mol. Neurodegener. 2013;8:23. PubMed PMC

Bhuripanyo K., Wang Y., Liu X., Zhou L., Liu R., Duong D., Zhao B., Bi Y., Zhou H., Chen G. Identifying the substrate proteins of U-box E3s E4B and CHIP by orthogonal ubiquitin transfer. Sci. Adv. 2018;4:e1701393. PubMed PMC

Bloom O., Evergren E., Tomilin N., Kjaerulff O., Löw P., Brodin L., Pieribone V., Greengard P., Shupliakov O. Colocalization of synapsin and actin during synaptic vesicle recycling. J Cell Biol. 2003;161:737–747. doi: 10.1083/jcb.200212140. PubMed DOI PMC

Bongiovanni A., Romancino D.P., Campos Y., Paterniti G., Qiu X., Moshiach S., Di Felice V., Vergani N., Ustek D., d'Azzo A. Alix protein is substrate of Ozz-E3 ligase and modulates actin remodeling in skeletal muscle. J. Biol. Chem. 2012;287:12159–12171. PubMed PMC

Borgonovo B., Cocucci E., Racchetti G., Podini P., Bachi A., Meldolesi J. Regulated exocytosis: a novel, widely expressed system. Nat. Cell Biol. 2002;4:955–962. PubMed

Bouchal P., Roumeliotis T., Hrstka R., Nenutil R., Vojtesek B., Garbis S.D. Biomarker discovery in low-grade breast cancer using isobaric stable isotope tags and two-dimensional liquid chromatography-tandem mass spectrometry (iTRAQ-2DLC-MS/MS) based quantitative proteomic analysis. J. Proteome Res. 2009;8:362–373. PubMed

Boucher E., Goldin-Blais L., Basiren Q., Mandato C.A. Actin dynamics and myosin contractility during plasma membrane repair and restoration: does one ring really heal them all? Curr. Top Membr. 2019;84:17–41. PubMed

Boucher E., Mandato C.A. Plasma membrane and cytoskeleton dynamics during single-cell wound healing. Biochim. Biophys. Acta. 2015;1853:2649–2661. PubMed

Bouter A., Gounou C., Bérat R., Tan S., Gallois B., Granier T., d'Estaintot B.L., Pöschl E., Brachvogel B., Brisson A.R. Annexin-A5 assembled into two-dimensional arrays promotes cell membrane repair. Nat. Commun. 2011;2:270. PubMed PMC

Boye T.L., Jeppesen J.C., Maeda K., Pezeshkian W., Solovyeva V., Nylandsted J., Simonsen A.C. Annexins induce curvature on free-edge membranes displaying distinct morphologies. Sci. Rep. 2018;8:10309. PubMed PMC

Bozelli J.C., Kamski-Hennekam E., Melacini G., Epand R.M. α-Synuclein and neuronal membranes: Conformational flexibilities in health and disease. Chem. Phys. Lipids. 2021;235:105034. PubMed

Cai C., Masumiya H., Weisleder N., Matsuda N., Nishi M., Hwang M., Ko J.K., Lin P., Thornton A., Zhao X. MG53 nucleates assembly of cell membrane repair machinery. Nat. Cell Biol. 2009;11:56–64. PubMed PMC

Chakrabarti A.M., Henser-Brownhill T., Monserrat J., Poetsch A.R., Luscombe N.M., Scaffidi P. Target-specific precision of CRISPR-mediated genome editing. Mol. Cell. 2019;73:699–713.e6. PubMed PMC

Chambers S.M., Fasano C.A., Papapetrou E.P., Tomishima M., Sadelain M., Studer L. Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling. Nat. Biotechnol. 2009;27:275–280. PubMed PMC

Cisternas F.A., Vincent J.B., Scherer S.W., Ray P.N. Cloning and characterization of human CADPS and CADPS2, new members of the Ca2+-dependent activator for secretion protein family. Genomics. 2003;81:279–291. PubMed

Connell P., Ballinger C.A., Jiang J., Wu Y., Thompson L.J., Höhfeld J., Patterson C. The co-chaperone CHIP regulates protein triage decisions mediated by heat-shock proteins. Nat. Cell Biol. 2001;3:93–96. PubMed

Cooper S.T., McNeil P.L. Membrane repair: mechanisms and pathophysiology. Physiol. Rev. 2015;95:1205–1240. PubMed PMC

Cummings B.S., Wills L.P., Schnellmann R.G. Measurement of cell death in Mammalian cells. Curr. Protoc. Pharmacol. 2012;12:2–3. Chapter 12, Unit12.18. PubMed

Dai Q., Zhang C., Wu Y., McDonough H., Whaley R.A., Godfrey V., Li H.H., Madamanchi N., Xu W., Neckers L. CHIP activates HSF1 and confers protection against apoptosis and cellular stress. EMBO J. 2003;22:5446–5458. PubMed PMC

Davenport N.R., Sonnemann K.J., Eliceiri K.W., Bement W.M. Membrane dynamics during cellular wound repair. Mol. Biol. Cell. 2016;27:2272–2285. PubMed PMC

de Groot N.S., Burgas M.T. Is membrane homeostasis the missing link between inflammation and neurodegenerative diseases? Cell Mol. Life Sci. 2015;72:4795–4805. PubMed PMC

Dettmer U., Ramalingam N., von Saucken V.E., Kim T.E., Newman A.J., Terry-Kantor E., Nuber S., Ericsson M., Fanning S., Bartels T. Loss of native α-synuclein multimerization by strategically mutating its amphipathic helix causes abnormal vesicle interactions in neuronal cells. Hum. Mol. Genet. 2017;26:3466–3481. PubMed PMC

Devine M.J., Ryten M., Vodicka P., Thomson A.J., Burdon T., Houlden H., Cavaleri F., Nagano M., Drummond N.J., Taanman J.W. Parkinson's disease induced pluripotent stem cells with triplication of the α-synuclein locus. Nat. Commun. 2011;2:440. PubMed PMC

Dickey C.A., Kamal A., Lundgren K., Klosak N., Bailey R.M., Dunmore J., Ash P., Shoraka S., Zlatkovic J., Eckman C.B. The high-affinity HSP90-CHIP complex recognizes and selectively degrades phosphorylated tau client proteins. J. Clin. Invest. 2007;117:648–658. PubMed PMC

Doshi B.M., Hightower L.E., Lee J. The role of Hsp27 and actin in the regulation of movement in human cancer cells responding to heat shock. Cell Stress Chaperones. 2009;14:445–457. PubMed PMC

Draeger A., Monastyrskaya K., Babiychuk E.B. Plasma membrane repair and cellular damage control: the annexin survival kit. Biochem. Pharmacol. 2011;81:703–712. PubMed

Drummond N.J., Davies N.O., Lovett J.E., Miller M.R., Cook G., Becker T., Becker C.G., McPhail D.B., Kunath T. A synthetic cell permeable antioxidant protects neurons against acute oxidative stress. Sci Rep. 2017;7 doi: 10.1038/s41598-017-12072-5. PubMed DOI PMC

Eden E., Lipson D., Yogev S., Yakhini Z. Discovering motifs in ranked lists of DNA sequences. PLoS Comput. Biol. 2007;3:e39. PubMed PMC

Eden E., Navon R., Steinfeld I., Lipson D., Yakhini Z. GOrilla: a tool for discovery and visualization of enriched GO terms in ranked gene lists. BMC Bioinformatics. 2009;10:48. PubMed PMC

Fais S., Luciani F., Logozzi M., Parlato S., Lozupone F. Linkage between cell membrane proteins and actin-based cytoskeleton: the cytoskeletal-driven cellular functions. Histol. Histopathol. 2000;15:539–549. PubMed

Faktor J., Bouchal P. [Building mass spectrometry spectral libraries of human cancer cell lines] Klin. Onkol. 2016;29(Suppl 4):54–58. PubMed

Gibb W.R., Luthert P.J., Janota I., Lantos P.L. Cortical Lewy body dementia: clinical features and classification. J. Neurol. Neurosurg. Psychiatry. 1989;52:185–192. PubMed PMC

Gov N.S. Guided by curvature: shaping cells by coupling curved membrane proteins and cytoskeletal forces. Philos. Trans. R. Soc. Lond. B Biol. Sci. 2018;373 doi: 10.1098/rstb.2017.0115. PubMed DOI PMC

Häger S.C., Nylandsted J. Annexins: players of single cell wound healing and regeneration. Commun. Integr. Biol. 2019;12:162–165. PubMed PMC

Huang d.W., Sherman B.T., Lempicki R.A. Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res. 2009;37:1–13. PubMed PMC

Huang d.W., Sherman B.T., Lempicki R.A. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat. Protoc. 2009;4:44–57. PubMed

Huang Q., Yang L., Luo J., Guo L., Wang Z., Yang X., Jin W., Fang Y., Ye J., Shan B. SWATH enables precise label-free quantification on proteome scale. Proteomics. 2015;15:1215–1223. PubMed

Ibañez-Vega J., Del Valle Batalla F., Saez J.J., Soza A., Yuseff M.I. Proteasome dependent actin remodeling facilitates antigen extraction at the immune synapse of B cells. Front. Immunol. 2019;10:225. PubMed PMC

Jaiswal J.K., Lauritzen S.P., Scheffer L., Sakaguchi M., Bunkenborg J., Simon S.M., Kallunki T., Jäättelä M., Nylandsted J. S100A11 is required for efficient plasma membrane repair and survival of invasive cancer cells. Nat. Commun. 2014;5:3795. PubMed PMC

Janco M., Bonello T.T., Byun A., Coster A.C., Lebhar H., Dedova I., Gunning P.W., Böcking T. The impact of tropomyosins on actin filament assembly is isoform specific. Bioarchitecture. 2016;6:61–75. PubMed PMC

Joshi V., Amanullah A., Upadhyay A., Mishra R., Kumar A., Mishra A. A decade of boon or burden: what has the CHIP ever done for cellular protein quality control mechanism implicated in neurodegeneration and aging? Front. Mol. Neurosci. 2016;9:93. PubMed PMC

Kaminska J., Spiess M., Stawiecka-Mirota M., Monkaityte R., Haguenauer-Tsapis R., Urban-Grimal D., Winsor B., Zoladek T. Yeast Rsp5 ubiquitin ligase affects the actin cytoskeleton in vivo and in vitro. Eur. J. Cell Biol. 2011;90:1016–1028. PubMed

Kampinga H.H., Kanon B., Salomons F.A., Kabakov A.E., Patterson C. Overexpression of the cochaperone CHIP enhances Hsp70-dependent folding activity in mammalian cells. Mol. Cell Biol. 2003;23:4948–4958. PubMed PMC

Kettern N., Rogon C., Limmer A., Schild H., Höhfeld J. The Hsc/Hsp70 co-chaperone network controls antigen aggregation and presentation during maturation of professional antigen presenting cells. PLoS One. 2011;6:e16398. PubMed PMC

Kevei É., Pokrzywa W., Hoppe T. Repair or destruction-an intimate liaison between ubiquitin ligases and molecular chaperones in proteostasis. FEBS Lett. 2017;591:2616–2635. PubMed PMC

Kitazawa H., Iida J., Uchida A., Haino-Fukushima K., Itoh T.J., Hotani H., Ookata K., Murofushi H., Bulinski J.C., Kishimoto T. Ser787 in the proline-rich region of human MAP4 is a critical phosphorylation site that reduces its activity to promote tubulin polymerization. Cell Struct. Funct. 2000;25:33–39. PubMed

Kolde R. 2019. Pheatmap: Pretty Heatmaps.

Kopp Y., Lang W.H., Schuster T.B., Martínez-Limón A., Hofbauer H.F., Ernst R., Calloni G., Vabulas R.M. CHIP as a membrane-shuttling proteostasis sensor. Elife. 2017;6 doi: 10.7554/eLife.29388. PubMed DOI PMC

Krämer A., Green J., Pollard J., Tugendreich S. Causal analysis approaches in ingenuity pathway analysis. Bioinformatics. 2014;30:523–530. PubMed PMC

Krause M., Dent E.W., Bear J.E., Loureiro J.J., Gertler F.B. Ena/VASP proteins: regulators of the actin cytoskeleton and cell migration. Annu. Rev. Cell Dev. Biol. 2003;19:541–564. PubMed

Landré V., Pion E., Narayan V., Xirodimas D.P., Ball K.L. DNA-binding regulates site-specific ubiquitination of IRF-1. Biochem. J. 2013;449:707–717. PubMed

Landré V., Revi B., Mir M.G., Verma C., Hupp T.R., Gilbert N., Ball K.L. Regulation of transcriptional activators by DNA-binding domain ubiquitination. Cell Death Differ. 2017;24:903–916. PubMed PMC

Lashuel H.A., Overk C.R., Oueslati A., Masliah E. The many faces of α-synuclein: from structure and toxicity to therapeutic target. Nat. Rev. Neurosci. 2013;14:38–48. PubMed PMC

Le Clainche C., Dwivedi S.P., Didry D., Carlier M.F. Vinculin is a dually regulated actin filament barbed end-capping and side-binding protein. J. Biol. Chem. 2010;285:23420–23432. PubMed PMC

Lecroisey C., Brouilly N., Qadota H., Mariol M.C., Rochette N.C., Martin E., Benian G.M., Ségalat L., Mounier N., Gieseler K. ZYX-1, the unique zyxin protein of Caenorhabditis elegans, is involved in dystrophin-dependent muscle degeneration. Mol. Biol. Cell. 2013;24:1232–1249. PubMed PMC

Love M.I., Huber W., Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15:550. PubMed PMC

MacGurn J.A., Hsu P.C., Emr S.D. Ubiquitin and membrane protein turnover: from cradle to grave. Annu. Rev. Biochem. 2012;81:231–259. PubMed

Marin R. The neuronal membrane as a key factor in neurodegeneration. Front. Physiol. 2013;4:188. PubMed PMC

Mark M.H. Lumping and splitting the Parkinson Plus syndromes: dementia with Lewy bodies, multiple system atrophy, progressive supranuclear palsy, and cortical-basal ganglionic degeneration. Neurol. Clin. 2001;19:607–627. vi. PubMed

Marques C., Guo W., Pereira P., Taylor A., Patterson C., Evans P.C., Shang F. The triage of damaged proteins: degradation by the ubiquitin-proteasome pathway or repair by molecular chaperones. FASEB J. 2006;20:741–743. PubMed PMC

Meacham G.C., Patterson C., Zhang W., Younger J.M., Cyr D.M. The Hsc70 co-chaperone CHIP targets immature CFTR for proteasomal degradation. Nat. Cell Biol. 2001;3:100–105. PubMed

Min J.N., Whaley R.A., Sharpless N.E., Lockyer P., Portbury A.L., Patterson C. CHIP deficiency decreases longevity, with accelerated aging phenotypes accompanied by altered protein quality control. Mol. Cell Biol. 2008;28:4018–4025. PubMed PMC

Miron T., Vancompernolle K., Vandekerckhove J., Wilchek M., Geiger B. A 25-kD inhibitor of actin polymerization is a low molecular mass heat shock protein. J. Cell Biol. 1991;114:255–261. PubMed PMC

Moe A.M., Golding A.E., Bement W.M. Cell healing: calcium, repair and regeneration. Semin. Cell Dev. Biol. 2015;45:18–23. PubMed PMC

Morishima Y., Wang A.M., Yu Z., Pratt W.B., Osawa Y., Lieberman A.P. CHIP deletion reveals functional redundancy of E3 ligases in promoting degradation of both signaling proteins and expanded glutamine proteins. Hum. Mol. Genet. 2008;17:3942–3952. PubMed PMC

Murata S., Minami Y., Minami M., Chiba T., Tanaka K. CHIP is a chaperone-dependent E3 ligase that ubiquitylates unfolded protein. EMBO Rep. 2001;2:1133–1138. PubMed PMC

Murtaza M., Jolly L.A., Gecz J., Wood S.A. La FAM fatale: USP9X in development and disease. Cell Mol. Life Sci. 2015;72:2075–2089. PubMed PMC

Narayan V., Landré V., Ning J., Hernychova L., Muller P., Verma C., Walkinshaw M.D., Blackburn E.A., Ball K.L. Protein-protein interactions modulate the docking-dependent E3-ubiquitin ligase activity of Carboxy-terminus of hsc70-interacting protein (CHIP) Mol. Cell Proteomics. 2015;14:2973–2987. PubMed PMC

Narayan V., Pion E., Landré V., Müller P., Ball K.L. Docking-dependent ubiquitination of the interferon regulatory factor-1 tumor suppressor protein by the ubiquitin ligase CHIP. J. Biol. Chem. 2011;286:607–619. PubMed PMC

Naudí A., Jové M., Ayala V., Portero-Otín M., Barja G., Pamplona R. Membrane lipid unsaturation as physiological adaptation to animal longevity. Front. Physiol. 2013;4:372. PubMed PMC

Naumanen P., Lappalainen P., Hotulainen P. Mechanisms of actin stress fibre assembly. J. Microsc. 2008;231:446–454. PubMed

Okiyoneda T., Barrière H., Bagdány M., Rabeh W.M., Du K., Höhfeld J., Young J.C., Lukacs G.L. Peripheral protein quality control removes unfolded CFTR from the plasma membrane. Science. 2010;329:805–810. PubMed PMC

Otey C.A., Pavalko F.M., Burridge K. An interaction between alpha-actinin and the beta 1 integrin subunit in vitro. J. Cell Biol. 1990;111:721–729. PubMed PMC

Paul I., Ghosh M.K. A CHIPotle in physiology and disease. Int. J. Biochem. Cell Biol. 2015;58:37–52. PubMed

Perez-Riverol Y., Csordas A., Bai J., Bernal-Llinares M., Hewapathirana S., Kundu D.J., Inuganti A., Griss J., Mayer G., Eisenacher M. The PRIDE database and related tools and resources in 2019: improving support for quantification data. Nucleic Acids Res. 2019;47:D442–D450. PubMed PMC

Qian S.B., McDonough H., Boellmann F., Cyr D.M., Patterson C. CHIP-mediated stress recovery by sequential ubiquitination of substrates and Hsp70. Nature. 2006;440:551–555. PubMed PMC

R-Core-Team . R Foundation for Statistical Computing; Vienna, Austria: 2018. R: A Language and Environment for Statistical Computing.

Ronnebaum S.M., Wu Y., McDonough H., Patterson C. The ubiquitin ligase CHIP prevents SirT6 degradation through noncanonical ubiquitination. Mol. Cell Biol. 2013;33:4461–4472. PubMed PMC

Rosenberger G., Koh C.C., Guo T., Röst H.L., Kouvonen P., Collins B.C., Heusel M., Liu Y., Caron E., Vichalkovski A. A repository of assays to quantify 10,000 human proteins by SWATH-MS. Sci. Data. 2014;1:140031. PubMed PMC

Rosser M.F., Washburn E., Muchowski P.J., Patterson C., Cyr D.M. Chaperone functions of the E3 ubiquitin ligase CHIP. J. Biol. Chem. 2007;282:22267–22277. PubMed

Rovere M., Powers A.E., Jiang H., Pitino J.C., Fonseca-Ornelas L., Patel D.S., Achille A., Langen R., Varkey J., Bartels T. E46K-like α-synuclein mutants increase lipid interactions and disrupt membrane selectivity. J. Biol. Chem. 2019;294:9799–9812. PubMed PMC

Schneider C.A., Rasband W.S., Eliceiri K.W. NIH Image to ImageJ: 25 years of image analysis. Nat Methods. 2012;9:671–675. doi: 10.1038/nmeth.2089. PubMed DOI PMC

Schuster S., Heuten E., Velic A., Admard J., Synofzik M., Ossowski S., Macek B., Hauser S., Schöls L. CHIP mutations affect the heat shock response differently in human fibroblasts and iPSC-derived neurons. Dis. Model. Mech. 2020;13 doi: 10.1242/dmm.045096. PubMed DOI PMC

Shi Y., Kirwan P., Livesey F.J. Directed differentiation of human pluripotent stem cells to cerebral cortex neurons and neural networks. Nat. Protoc. 2012;7:1836–1846. PubMed

Shi Y., Kirwan P., Smith J., Robinson H.P., Livesey F.J. Human cerebral cortex development from pluripotent stem cells to functional excitatory synapses. Nat. Neurosci. 2012;15:477–486. S471. PubMed PMC

Shin Y., Klucken J., Patterson C., Hyman B.T., McLean P.J. The co-chaperone carboxyl terminus of Hsp70-interacting protein (CHIP) mediates alpha-synuclein degradation decisions between proteasomal and lysosomal pathways. J. Biol. Chem. 2005;280:23727–23734. PubMed

Shrivastava A.N., Aperia A., Melki R., Triller A. Physico-pathologic mechanisms involved in neurodegeneration: misfolded protein-plasma membrane interactions. Neuron. 2017;95:33–50. PubMed

Silvestre J.G., Baptista I.L., Silva W.J., Cruz A., Silva M.T., Miyabara E.H., Labeit S., Moriscot A.S. The E3 ligase MuRF2 plays a key role in the functional capacity of skeletal muscle fibroblasts. Braz. J. Med. Biol. Res. 2019;52:e8551. PubMed PMC

Simonsen A.C., Boye T.L., Nylandsted J. Annexins bend wound edges during plasma membrane repair. Curr. Med. Chem. 2020;27:3600–3610. doi: 10.2174/0929867326666190121121143. PubMed DOI

Sønder S.L., Boye T.L., Tölle R., Dengjel J., Maeda K., Jäättelä M., Simonsen A.C., Jaiswal J.K., Nylandsted J. Annexin A7 is required for ESCRT III-mediated plasma membrane repair. Sci. Rep. 2019;9:6726. PubMed PMC

Stawiecka-Mirota M., Kamińska J., Urban-Grimal D., Haines D.S., Zoładek T. Nedd4, a human ubiquitin ligase, affects actin cytoskeleton in yeast cells. Exp. Cell Res. 2008;314:3318–3325. PubMed

Sugita S., Janz R., Südhof T.C. Synaptogyrins regulate Ca2+-dependent exocytosis in PC12 cells. J. Biol. Chem. 1999;274:18893–18901. PubMed

Supek F., Bošnjak M., Škunca N., Šmuc T. REVIGO summarizes and visualizes long lists of gene ontology terms. PLoS One. 2011;6:e21800. PubMed PMC

Szklarczyk D., Gable A.L., Lyon D., Junge A., Wyder S., Huerta-Cepas J., Simonovic M., Doncheva N.T., Morris J.H., Bork P. STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 2019;47:D607–D613. PubMed PMC

Tawo R., Pokrzywa W., Kevei É., Akyuz M.E., Balaji V., Adrian S., Höhfeld J., Hoppe T. The ubiquitin ligase CHIP integrates proteostasis and aging by regulation of insulin receptor turnover. Cell. 2017;169:470–482.e13. PubMed PMC

Wang W., Zhou Z., Xiang L., Lv M., Ni T., Deng J., Wang H., Masatara S., Zhou Y., Liu Y. CHIP-mediated ubiquitination of Galectin-1 predicts colorectal cancer prognosis. Int. J. Biol. Sci. 2020;16:719–729. PubMed PMC

Watanabe Y., Sasahara Y., Ramesh N., Massaad M.J., Yeng Looi C., Kumaki S., Kure S., Geha R.S., Tsuchiya S. T-cell receptor ligation causes Wiskott-Aldrich syndrome protein degradation and F-actin assembly downregulation. J. Allergy Clin. Immunol. 2013;132:648–655.e1. PubMed

Way L., Faktor J., Dvorakova P., Nicholson J., Vojtesek B., Graham D., Ball K.L., Hupp T. Rearrangement of mitochondrial pyruvate dehydrogenase subunit dihydrolipoamide dehydrogenase protein-protein interactions by the MDM2 ligand nutlin-3. Proteomics. 2016;16:2327–2344. PubMed PMC

Wiśniewski J.R., Zougman A., Nagaraj N., Mann M. Universal sample preparation method for proteome analysis. Nat. Methods. 2009;6:359–362. PubMed

Wong-Ekkabut J., Xu Z., Triampo W., Tang I.M., Tieleman D.P., Monticelli L. Effect of lipid peroxidation on the properties of lipid bilayers: a molecular dynamics study. Biophys. J. 2007;93:4225–4236. PubMed PMC

Xicoy H., Wieringa B., Martens G.J. The SH-SY5Y cell line in Parkinson's disease research: a systematic review. Mol. Neurodegener. 2017;12:10. PubMed PMC

Yadav R., Vattepu R., Beck M.R. Phosphoinositide binding inhibits actin crosslinking and polymerization by palladin. J. Mol. Biol. 2016;428:4031–4047. PubMed PMC

Yang M., Wang C., Zhu X., Tang S., Shi L., Cao X., Chen T. E3 ubiquitin ligase CHIP facilitates Toll-like receptor signaling by recruiting and polyubiquitinating Src and atypical PKC{zeta} J. Exp. Med. 2011;208:2099–2112. PubMed PMC

Yue J., Huhn S., Shen Z. Complex roles of filamin-A mediated cytoskeleton network in cancer progression. Cell Biosci. 2013;3:7. PubMed PMC

Zhan S., Wang T., Ge W. Multiple functions of the E3 ubiquitin ligase CHIP in immunity. Int. Rev. Immunol. 2017;36:300–312. PubMed

Zhang H., Amick J., Chakravarti R., Santarriaga S., Schlanger S., McGlone C., Dare M., Nix J.C., Scaglione K.M., Stuehr D.J. A bipartite interaction between Hsp70 and CHIP regulates ubiquitination of chaperoned client proteins. Structure. 2015;23:472–482. PubMed PMC

Zhang M., Windheim M., Roe S.M., Peggie M., Cohen P., Prodromou C., Pearl L.H. Chaperoned ubiquitylation--crystal structures of the CHIP U box E3 ubiquitin ligase and a CHIP-Ubc13-Uev1a complex. Mol. Cell. 2005;20:525–538. PubMed

Zhao B., Sun G., Feng G., Duan W., Zhu X., Chen S., Hou L., Jin Z., Yi D. Carboxy terminus of heat shock protein (HSP) 70-interacting protein (CHIP) inhibits HSP70 in the heart. J. Physiol. Biochem. 2012;68:485–491. PubMed

Zhao Y., Macgurn J.A., Liu M., Emr S. The ART-Rsp5 ubiquitin ligase network comprises a plasma membrane quality control system that protects yeast cells from proteotoxic stress. Elife. 2013;2:e00459. PubMed PMC

Nita, E. (2016). Role of CHIP in the proteome of a neuronal cell model. MSc (University of Edinburgh).

Generation of a CHIP isogenic human iPSC-derived cortical neuron model for functional proteomics