KPNB1 modulates the Machado-Joseph disease protein ataxin-3 through activation of the mitochondrial protease CLPP.
Ataxin-3
Karyopherins
Mitochondrial protease CLPP
Polyglutamine diseases
Proteolysis
Spinocerebellar ataxia type 3
Journal
Cellular and molecular life sciences : CMLS
ISSN: 1420-9071
Titre abrégé: Cell Mol Life Sci
Pays: Switzerland
ID NLM: 9705402
Informations de publication
Date de publication:
06 Jul 2022
06 Jul 2022
Historique:
received:
20
12
2021
accepted:
11
05
2022
revised:
25
04
2022
entrez:
6
7
2022
pubmed:
7
7
2022
medline:
9
7
2022
Statut:
epublish
Résumé
Machado-Joseph disease (MJD) is characterized by a pathological expansion of the polyglutamine (polyQ) tract within the ataxin-3 protein. Despite its primarily cytoplasmic localization, polyQ-expanded ataxin-3 accumulates in the nucleus and forms intranuclear aggregates in the affected neurons. Due to these histopathological hallmarks, the nucleocytoplasmic transport machinery has garnered attention as an important disease relevant mechanism. Here, we report on MJD cell model-based analysis of the nuclear transport receptor karyopherin subunit beta-1 (KPNB1) and its implications in the molecular pathogenesis of MJD. Although directly interacting with both wild-type and polyQ-expanded ataxin-3, modulating KPNB1 did not alter the intracellular localization of ataxin-3. Instead, overexpression of KPNB1 reduced ataxin-3 protein levels and the aggregate load, thereby improving cell viability. On the other hand, its knockdown and inhibition resulted in the accumulation of soluble and insoluble ataxin-3. Interestingly, the reduction of ataxin-3 was apparently based on protein fragmentation independent of the classical MJD-associated proteolytic pathways. Label-free quantitative proteomics and knockdown experiments identified mitochondrial protease CLPP as a potential mediator of the ataxin-3-degrading effect induced by KPNB1. We confirmed reduction of KPNB1 protein levels in MJD by analyzing two MJD transgenic mouse models and induced pluripotent stem cells (iPSCs) derived from MJD patients. Our results reveal a yet undescribed regulatory function of KPNB1 in controlling the turnover of ataxin-3, thereby highlighting a new potential target of therapeutic value for MJD.
Identifiants
pubmed: 35794401
doi: 10.1007/s00018-022-04372-5
pii: 10.1007/s00018-022-04372-5
pmc: PMC9259533
doi:
Substances chimiques
Kpnb1 protein, mouse
0
Nerve Tissue Proteins
0
Nuclear Proteins
0
beta Karyopherins
0
Endopeptidases
EC 3.4.-
Ataxin-3
EC 3.4.19.12
Atxn3 protein, mouse
EC 3.4.19.12
CLPP protein, mouse
EC 3.4.21.92
Endopeptidase Clp
EC 3.4.21.92
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
401Subventions
Organisme : Federal Ministry of Education and Research (BMBF)
ID : 57129429
Organisme : German Academic Exchange Service (DAAD)
ID : 01DN18020
Informations de copyright
© 2022. The Author(s).
Références
Hipp MS, Kasturi P, Hartl FU (2019) The proteostasis network and its decline in ageing. Nat Rev Mol Cell Biol 20:421–435
pubmed: 30733602
Bauer PO, Nukina N (2009) The pathogenic mechanisms of polyglutamine diseases and current therapeutic strategies. J Neurochem 110:1737–1765
pubmed: 19650870
McLoughlin HS, Moore LR, Paulson HL (2020) Pathogenesis of SCA3 and implications for other polyglutamine diseases. Neurobiol Dis 134:104635
pubmed: 31669734
Yushchenko T, Deuerling E, Hauser K (2018) Insights into the aggregation mechanism of PolyQ proteins with different glutamine repeat lengths. Biophys J 114:1847–1857
pubmed: 29694863
pmcid: 5937114
Alves-Rodrigues A, Gregori L, Figueiredo-Pereira ME (1998) Ubiquitin, cellular inclusions and their role in neurodegeneration. Trends Neurosci 21:516–520
pubmed: 9881849
Cummings CJ, Mancini MA, Antalffy B, DeFranco DB, Orr HT, Zoghbi HY (1998) Chaperone suppression of aggregation and altered subcellular proteasome localization imply protein misfolding in SCA1. Nat Genet 19:148–154
pubmed: 9620770
Perez MK, Paulson HL, Pendse SJ, Saionz SJ, Bonini NM, Pittman RN (1998) Recruitment and the role of nuclear localization in polyglutamine-mediated aggregation. J Cell Biol 143:1457–1470
pubmed: 9852144
pmcid: 2132986
Schmidt T, Lindenberg KS, Krebs A, Schöls L, Laccone F, Herms J, Rechsteiner M, Riess O, Landwehrmeyer GB (2002) Protein surveillance machinery in brains with spinocerebellar ataxia type 3: redistribution and differential recruitment of 26S proteasome subunits and chaperones to neuronal intranuclear inclusions. Ann Neurol 51:302–310
pubmed: 11891825
Rudnicki DD, Margolis RL (2003) Repeat expansion and autosomal dominant neurodegenerative disorders: consensus and controversy. Expert Rev Mol Med 5:1–24
pubmed: 14585172
Kawaguchi Y, Okamoto T, Taniwaki M, Aizawa M, Inoue M, Katayama S, Kawakami H, Nakamura S, Nishimura M, Akiguchi I et al (1994) CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1. Nat Genet 8:221–228
pubmed: 7874163
Schöls L, Bauer P, Schmidt T, Schulte T, Riess O (2004) Autosomal dominant cerebellar ataxias: clinical features, genetics, and pathogenesis. Lancet Neurol 3:291–304
pubmed: 15099544
Riess O, Rüb U, Pastore A, Bauer P, Schöls L (2008) SCA3: neurological features, pathogenesis and animal models. Cerebellum 7:125–137
pubmed: 18418689
Maciel P, Costa MC, Ferro A, Rousseau M, Santos CS, Gaspar C, Barros J, Rouleau GA, Coutinho P, Sequeiros J (2001) Improvement in the molecular diagnosis of Machado–Joseph disease. Arch Neurol 58:1821–1827
pubmed: 11708990
Burnett B, Li F, Pittman RN (2003) The polyglutamine neurodegenerative protein ataxin-3 binds polyubiquitylated proteins and has ubiquitin protease activity. Hum Mol Genet 12:3195–3205
pubmed: 14559776
Da Silva JD, Teixeira-Castro A, Maciel P (2019) From pathogenesis to novel therapeutics for spinocerebellar ataxia Type 3: evading potholes on the way to translation. Neurotherapeutics 16:1009–1031
pubmed: 31691128
pmcid: 6985322
Costa Mdo C, Paulson HL (2012) Toward understanding Machado–Joseph disease. Prog Neurobiol 97:239–257
pubmed: 22133674
Simões AT, Gonçalves N, Koeppen A, Déglon N, Kügler S, Duarte CB (2012) Pereira de Almeida L: Calpastatin-mediated inhibition of calpains in the mouse brain prevents mutant ataxin 3 proteolysis, nuclear localization and aggregation, relieving Machado–Joseph disease. Brain 135:2428–2439
pubmed: 22843411
Weber JJ, Golla M, Guaitoli G, Wanichawan P, Hayer SN, Hauser S, Krahl AC, Nagel M, Samer S, Aronica E et al (2017) A combinatorial approach to identify calpain cleavage sites in the Machado-Joseph disease protein ataxin-3. Brain 140:1280–1299
pubmed: 28334907
Trottier Y, Cancel G, An-Gourfinkel I, Lutz Y, Weber C, Brice A, Hirsch E, Mandel JL (1998) Heterogeneous intracellular localization and expression of ataxin-3. Neurobiol Dis 5:335–347
pubmed: 10069576
Schmidt T, Landwehrmeyer GB, Schmitt I, Trottier Y, Auburger G, Laccone F, Klockgether T, Völpel M, Epplen JT, Schöls L, Riess O (1998) An isoform of ataxin-3 accumulates in the nucleus of neuronal cells in affected brain regions of SCA3 patients. Brain Pathol 8:669–679
pubmed: 9804376
Yang W, Dunlap JR, Andrews RB, Wetzel R (2002) Aggregated polyglutamine peptides delivered to nuclei are toxic to mammalian cells. Hum Mol Genet 11:2905–2917
pubmed: 12393802
Bichelmeier U, Schmidt T, Hübener J, Boy J, Rüttiger L, Häbig K, Poths S, Bonin M, Knipper M, Schmidt WJ et al (2007) Nuclear localization of ataxin-3 is required for the manifestation of symptoms in SCA3: in vivo evidence. J Neurosci 27:7418–7428
pubmed: 17626202
pmcid: 6672614
Chook YM, Süel KE (2011) Nuclear import by karyopherin-βs: recognition and inhibition. Biochim Biophys Acta 1813:1593–1606
pubmed: 21029754
Cautain B, Hill R, de Pedro N, Link W (2015) Components and regulation of nuclear transport processes. Febs j 282:445–462
pubmed: 25429850
Antony PM, Mäntele S, Mollenkopf P, Boy J, Kehlenbach RH, Riess O, Schmidt T (2009) Identification and functional dissection of localization signals within ataxin-3. Neurobiol Dis 36:280–292
pubmed: 19660550
Breuer P, Haacke A, Evert BO, Wüllner U (2010) Nuclear aggregation of polyglutamine-expanded ataxin-3: fragments escape the cytoplasmic quality control. J Biol Chem 285:6532–6537
pubmed: 20064935
pmcid: 2825449
Sowa AS, Martin E, Martins IM, Schmidt J, Depping R, Weber JJ, Rother F, Hartmann E, Bader M, Riess O et al (2018) Karyopherin α-3 is a key protein in the pathogenesis of spinocerebellar ataxia type 3 controlling the nuclear localization of ataxin-3. Proc Natl Acad Sci USA 115:E2624-e2633
pubmed: 29476013
pmcid: 5856529
Cemal CK, Carroll CJ, Lawrence L, Lowrie MB, Ruddle P, Al-Mahdawi S, King RH, Pook MA, Huxley C, Chamberlain S (2002) YAC transgenic mice carrying pathological alleles of the MJD1 locus exhibit a mild and slowly progressive cerebellar deficit. Hum Mol Genet 11:1075–1094
pubmed: 11978767
Schmidt J, Mayer AK, Bakula D, Freude J, Weber JJ, Weiss A, Riess O, Schmidt T (2019) Vulnerability of frontal brain neurons for the toxicity of expanded ataxin-3. Hum Mol Genet 28:1463–1473
pubmed: 30576445
Gossen M, Bujard H (1992) Tight control of gene expression in mammalian cells by tetracycline-responsive promoters. Proc Natl Acad Sci USA 89:5547–5551
pubmed: 1319065
pmcid: 49329
Bayliss R, Littlewood T, Stewart M (2000) Structural basis for the interaction between FxFG nucleoporin repeats and importin-beta in nuclear trafficking. Cell 102:99–108
pubmed: 10929717
Weishäupl D, Schneider J, Peixoto Pinheiro B, Ruess C, Dold SM, von Zweydorf F, Gloeckner CJ, Schmidt J, Riess O, Schmidt T (2019) Physiological and pathophysiological characteristics of ataxin-3 isoforms. J Biol Chem 294:644–661
pubmed: 30455355
Hayer SN, Schelling Y, Huebener-Schmid J, Weber JJ, Hauser S, Schöls L (2018) Generation of an induced pluripotent stem cell line from a patient with spinocerebellar ataxia type 3 (SCA3): HIHCNi002-A. Stem Cell Res 30:171–174
pubmed: 29936336
Suzuki K, Bose P, Leong-Quong RY, Fujita DJ, Riabowol K (2010) REAP: a two minute cell fractionation method. BMC Res Notes 3:294
pubmed: 21067583
pmcid: 2993727
Borchert N, Dieterich C, Krug K, Schütz W, Jung S, Nordheim A, Sommer RJ, Macek B (2010) Proteogenomics of Pristionchus pacificus reveals distinct proteome structure of nematode models. Genome Res 20:837–846
pubmed: 20237107
pmcid: 2877580
Rappsilber J, Mann M, Ishihama Y (2007) Protocol for micro-purification, enrichment, pre-fractionation and storage of peptides for proteomics using StageTips. Nat Protoc 2:1896–1906
pubmed: 17703201
Franz-Wachtel M, Eisler SA, Krug K, Wahl S, Carpy A, Nordheim A, Pfizenmaier K, Hausser A, Macek B (2012) Global detection of protein kinase D-dependent phosphorylation events in nocodazole-treated human cells. Mol Cell Proteomics 11:160–170
pubmed: 22496350
pmcid: 3418846
Cox J, Mann M (2008) MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat Biotechnol 26:1367–1372
pubmed: 19029910
Cox J, Neuhauser N, Michalski A, Scheltema RA, Olsen JV, Mann M (2011) Andromeda: a peptide search engine integrated into the MaxQuant environment. J Proteome Res 10:1794–1805
pubmed: 21254760
Elias JE, Gygi SP (2007) Target-decoy search strategy for increased confidence in large-scale protein identifications by mass spectrometry. Nat Methods 4:207–214
pubmed: 17327847
Luber CA, Cox J, Lauterbach H, Fancke B, Selbach M, Tschopp J, Akira S, Wiegand M, Hochrein H, O’Keeffe M, Mann M (2010) Quantitative proteomics reveals subset-specific viral recognition in dendritic cells. Immunity 32:279–289
pubmed: 20171123
Tyanova S, Temu T, Sinitcyn P, Carlson A, Hein MY, Geiger T, Mann M, Cox J (2016) The Perseus computational platform for comprehensive analysis of (prote)omics data. Nat Methods 13:731–740
pubmed: 27348712
Damelin M, Silver PA (2000) Mapping interactions between nuclear transport factors in living cells reveals pathways through the nuclear pore complex. Mol Cell 5:133–140
pubmed: 10678175
Soderholm JF, Bird SL, Kalab P, Sampathkumar Y, Hasegawa K, Uehara-Bingen M, Weis K, Heald R (2011) Importazole, a small molecule inhibitor of the transport receptor importin-β. ACS Chem Biol 6:700–708
pubmed: 21469738
pmcid: 3137676
Weber JJ, Sowa AS, Binder T, Hübener J (2014) From pathways to targets: understanding the mechanisms behind polyglutamine disease. Biomed Res Int 2014:701758
pubmed: 25309920
pmcid: 4189765
Pereira Sena P, Weber JJ, Watchon M, Robinson KJ, Wassouf Z, Hauser S, Helm J, Abeditashi M, Schmidt J, Hübener-Schmid J et al (2021) Pathophysiological interplay between O-GlcNAc transferase and the Machado-Joseph disease protein ataxin-3. Proc Natl Acad Sci USA 118(47):e2025810118
Blount JR, Tsou WL, Ristic G, Burr AA, Ouyang M, Galante H, Scaglione KM, Todi SV (2014) Ubiquitin-binding site 2 of ataxin-3 prevents its proteasomal degradation by interacting with Rad23. Nat Commun 5:4638
pubmed: 25144244
Berke SJ, Schmied FA, Brunt ER, Ellerby LM, Paulson HL (2004) Caspase-mediated proteolysis of the polyglutamine disease protein ataxin-3. J Neurochem 89:908–918
pubmed: 15140190
Yan XX, Jeromin A, Jeromin A (2012) Spectrin breakdown products (SBDPs) as potential biomarkers for neurodegenerative diseases. Curr Transl Geriatr Exp Gerontol Rep 1:85–93
pubmed: 23710421
pmcid: 3661686
Schmidt J, Schmidt T, Golla M, Lehmann L, Weber JJ, Hübener-Schmid J, Riess O (2016) In vivo assessment of riluzole as a potential therapeutic drug for spinocerebellar ataxia type 3. J Neurochem 138:150–162
pubmed: 26990650
Yu AY, Houry WA (2007) ClpP: a distinctive family of cylindrical energy-dependent serine proteases. FEBS Lett 581:3749–3757
pubmed: 17499722
Ding B, Sepehrimanesh M (2021) Nucleocytoplasmic transport: regulatory mechanisms and the implications in neurodegeneration. Int J Mol Sci 22(8):4165
pubmed: 33920577
pmcid: 8072611
Grima JC, Daigle JG, Arbez N, Cunningham KC, Zhang K, Ochaba J, Geater C, Morozko E, Stocksdale J, Glatzer JC et al (2017) Mutant huntingtin disrupts the nuclear pore complex. Neuron 94:93-107.e106
pubmed: 28384479
pmcid: 5595097
Aizawa H, Yamashita T, Kato H, Kimura T, Kwak S (2019) Impaired nucleoporins are present in sporadic amyotrophic lateral sclerosis motor neurons that exhibit mislocalization of the 43-kDa TAR DNA-binding protein. J Clin Neurol 15:62–67
pubmed: 30618218
Eftekharzadeh B, Daigle JG, Kapinos LE, Coyne A, Schiantarelli J, Carlomagno Y, Cook C, Miller SJ, Dujardin S, Amaral AS et al (2018) Tau protein disrupts nucleocytoplasmic transport in Alzheimer’s disease. Neuron 99:925-940.e927
pubmed: 30189209
pmcid: 6240334
Chen V, Moncalvo M, Tringali D, Tagliafierro L, Shriskanda A, Ilich E, Dong W, Kantor B, Chiba-Falek O (2020) The mechanistic role of alpha-synuclein in the nucleus: impaired nuclear function caused by familial Parkinson’s disease SNCA mutations. Hum Mol Genet 29:3107–3121
pubmed: 32954426
pmcid: 7645704
Zhang K, Donnelly CJ, Haeusler AR, Grima JC, Machamer JB, Steinwald P, Daley EL, Miller SJ, Cunningham KM, Vidensky S et al (2015) The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature 525:56–61
pubmed: 26308891
pmcid: 4800742
Zhang S, Williamson NA, Duvick L, Lee A, Orr HT, Korlin-Downs A, Yang P, Mok YF, Jans DA, Bogoyevitch MA (2020) The ataxin-1 interactome reveals direct connection with multiple disrupted nuclear transport pathways. Nat Commun 11:3343
pubmed: 32620905
pmcid: 7334205
Havel LS, Li S, Li XJ (2009) Nuclear accumulation of polyglutamine disease proteins and neuropathology. Mol Brain 2:21
pubmed: 19575804
pmcid: 2714308
Tydlacka S, Wang CE, Wang X, Li S, Li XJ (2008) Differential activities of the ubiquitin-proteasome system in neurons versus glia may account for the preferential accumulation of misfolded proteins in neurons. J Neurosci 28:13285–13295
pubmed: 19052220
pmcid: 2662777
Colomer Gould VF, Goti D, Pearce D, Gonzalez GA, Gao H, Bermudez de Leon M, Jenkins NA, Copeland NG, Ross CA, Brown DR (2007) A mutant ataxin-3 fragment results from processing at a site N-terminal to amino acid 190 in brain of Machado-Joseph disease-like transgenic mice. Neurobiol Dis 27:362–369
pubmed: 17632007
pmcid: 2040168
Matos CA, Almeida LP, Nobrega C (2017) Proteolytic cleavage of polyglutamine disease-causing proteins: revisiting the toxic fragment hypothesis. Curr Pharm Des 23:753–775
pubmed: 28025946
Pozzi C, Valtorta M, Tedeschi G, Galbusera E, Pastori V, Bigi A, Nonnis S, Grassi E, Fusi P (2008) Study of subcellular localization and proteolysis of ataxin-3. Neurobiol Dis 30:190–200
pubmed: 18353661
Fischer F, Langer JD, Osiewacz HD (2015) Identification of potential mitochondrial CLPXP protease interactors and substrates suggests its central role in energy metabolism. Sci Rep 5:18375
pubmed: 26679294
pmcid: 4683621
Szczepanowska K, Maiti P, Kukat A, Hofsetz E, Nolte H, Senft K, Becker C, Ruzzenente B, Hornig-Do HT, Wibom R et al (2016) CLPP coordinates mitoribosomal assembly through the regulation of ERAL1 levels. EMBO J 35:2566–2583
pubmed: 27797820
pmcid: 5283601
Hu D, Sun X, Liao X, Zhang X, Zarabi S, Schimmer A, Hong Y, Ford C, Luo Y, Qi X (2019) Alpha-synuclein suppresses mitochondrial protease ClpP to trigger mitochondrial oxidative damage and neurotoxicity. Acta Neuropathol 137:939–960
pubmed: 30877431
pmcid: 6531426
Kristensen LV, Oppermann FS, Rauen MJ, Fog K, Schmidt T, Schmidt J, Harmuth T, Hartmann-Petersen R, Thirstrup K (2018) Mass spectrometry analyses of normal and polyglutamine expanded ataxin-3 reveal novel interaction partners involved in mitochondrial function. Neurochem Int 112:5–17
pubmed: 29111377
Laço MN, Oliveira CR, Paulson HL, Rego AC (2012) Compromised mitochondrial complex II in models of Machado-Joseph disease. Biochim Biophys Acta 1822:139–149
pubmed: 22037589
Mosammaparast N, Pemberton LF (2004) Karyopherins: from nuclear-transport mediators to nuclear-function regulators. Trends Cell Biol 14:547–556
pubmed: 15450977
Zhong Y, Wang Y, Yang H, Ballar P, Lee JG, Ye Y, Monteiro MJ, Fang S (2011) Importin beta interacts with the endoplasmic reticulum-associated degradation machinery and promotes ubiquitination and degradation of mutant alpha1-antitrypsin. J Biol Chem 286:33921–33930
pubmed: 21832065
pmcid: 3190800
Harel A, Forbes DJ (2004) Importin beta: conducting a much larger cellular symphony. Mol Cell 16:319–330
pubmed: 15525506
van der Watt PJ, Maske CP, Hendricks DT, Parker MI, Denny L, Govender D, Birrer MJ, Leaner VD (2009) The Karyopherin proteins, Crm1 and Karyopherin beta1, are overexpressed in cervical cancer and are critical for cancer cell survival and proliferation. Int J Cancer 124:1829–1840
pubmed: 19117056
pmcid: 6944291
Kuusisto HV, Jans DA (2015) Hyper-dependence of breast cancer cell types on the nuclear transporter Importin β1. Biochim Biophys Acta 1853:1870–1878
pubmed: 25960398
Yang L, Hu B, Zhang Y, Qiang S, Cai J, Huang W, Gong C, Zhang T, Zhang S, Xu P et al (2015) Suppression of the nuclear transporter-KPNβ1 expression inhibits tumor proliferation in hepatocellular carcinoma. Med Oncol 32:128
pubmed: 25794490
Kodama M, Kodama T, Newberg JY, Katayama H, Kobayashi M, Hanash SM, Yoshihara K, Wei Z, Tien JC, Rangel R et al (2017) In vivo loss-of-function screens identify KPNB1 as a new druggable oncogene in epithelial ovarian cancer. Proc Natl Acad Sci USA 114:E7301-e7310
pubmed: 28811376
pmcid: 5584430
Bouchnak I, van Wijk KJ (2021) Structure, function, and substrates of Clp AAA+ protease systems in cyanobacteria, plastids, and apicoplasts: a comparative analysis. J Biol Chem 296:100338
pubmed: 33497624
pmcid: 7966870