Rhes, a striatal enriched protein, regulates post-translational small-ubiquitin-like-modifier (SUMO) modification of nuclear proteins and alters gene expression.
Brain
Differentiation
Gene regulation
Medium spiny neuron
Morphology
Perinuclear membrane
SUMO E3-ligase
Signaling
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:
08 Apr 2024
08 Apr 2024
Historique:
received:
27
10
2023
accepted:
20
02
2024
revised:
26
01
2024
medline:
9
4
2024
pubmed:
9
4
2024
entrez:
8
4
2024
Statut:
epublish
Résumé
Rhes (Ras homolog enriched in the striatum), a multifunctional protein that regulates striatal functions associated with motor behaviors and neurological diseases, can shuttle from cell to cell via the formation of tunneling-like nanotubes (TNTs). However, the mechanisms by which Rhes mediates diverse functions remain unclear. Rhes is a small GTPase family member which contains a unique C-terminal Small Ubiquitin-like Modifier (SUMO) E3-like domain that promotes SUMO post-translational modification of proteins (SUMOylation) by promoting "cross-SUMOylation" of the SUMO enzyme SUMO E1 (Aos1/Uba2) and SUMO E2 ligase (Ubc-9). Nevertheless, the identity of the SUMO substrates of Rhes remains largely unknown. Here, by combining high throughput interactome and SUMO proteomics, we report that Rhes regulates the SUMOylation of nuclear proteins that are involved in the regulation of gene expression. Rhes increased the SUMOylation of histone deacetylase 1 (HDAC1) and histone 2B, while decreasing SUMOylation of heterogeneous nuclear ribonucleoprotein M (HNRNPM), protein polybromo-1 (PBRM1) and E3 SUMO-protein ligase (PIASy). We also found that Rhes itself is SUMOylated at 6 different lysine residues (K32, K110, K114, K120, K124, and K245). Furthermore, Rhes regulated the expression of genes involved in cellular morphogenesis and differentiation in the striatum, in a SUMO-dependent manner. Our findings thus provide evidence for a previously undescribed role for Rhes in regulating the SUMOylation of nuclear targets and in orchestrating striatal gene expression via SUMOylation.
Identifiants
pubmed: 38589732
doi: 10.1007/s00018-024-05181-8
pii: 10.1007/s00018-024-05181-8
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
169Subventions
Organisme : NINDS NIH HHS
ID : R01-NS087019-01A1
Pays : United States
Organisme : NINDS NIH HHS
ID : R01-NS094577-01A1
Pays : United States
Organisme : NINDS NIH HHS
ID : 3R01NS128225-02S1
Pays : United States
Organisme : NINDS NIH HHS
ID : 1R21NS128564-01
Pays : United States
Informations de copyright
© 2024. The Author(s).
Références
Harrison LM (2012) Rhes: a GTP-binding protein integral to striatal physiology and pathology. Cell Mol Neurobiol 32(6):907–918
pubmed: 22450871
pmcid: 3396771
doi: 10.1007/s10571-012-9830-6
Usui H et al (1994) Isolation of clones of rat striatum-specific mRNAs by directional tag PCR subtraction. J Neurosci 14(8):4915–4926
pubmed: 8046460
pmcid: 6577190
doi: 10.1523/JNEUROSCI.14-08-04915.1994
Sciamanna G et al (2015) Rhes regulates dopamine D2 receptor transmission in striatal cholinergic interneurons. Neurobiol Dis 78:146–161
pubmed: 25818655
doi: 10.1016/j.nbd.2015.03.021
Subramaniam S (2022) Striatal Induction and Spread of the Huntington's Disease Protein: A Novel Rhes Route. J Huntingtons Dis
Vargiu P et al (2004) The small GTP-binding protein, Rhes, regulates signal transduction from G protein-coupled receptors. Oncogene 23(2):559–568
pubmed: 14724584
doi: 10.1038/sj.onc.1207161
Errico F et al (2008) The GTP-binding protein Rhes modulates dopamine signalling in striatal medium spiny neurons. Mol Cell Neurosci 37(2):335–345
pubmed: 18035555
doi: 10.1016/j.mcn.2007.10.007
Ghiglieri V et al (2015) Rhes influences striatal cAMP/PKA-dependent signaling and synaptic plasticity in a gender-sensitive fashion. Sci Rep 5:10933
pubmed: 26190541
pmcid: 4507147
doi: 10.1038/srep10933
Harrison LM, He Y (2011) Rhes and AGS1/Dexras1 affect signaling by dopamine D1 receptors through adenylyl cyclase. J Neurosci Res 89(6):874–882
pubmed: 21374700
pmcid: 3077464
doi: 10.1002/jnr.22604
Shahani N et al (2016) RasGRP1 promotes amphetamine-induced motor behavior through a Rhes interaction network (“Rhesactome”) in the striatum. Sci Signal 9(454):ra111
pubmed: 27902448
pmcid: 5142824
doi: 10.1126/scisignal.aaf6670
Subramaniam S et al (2011) Rhes, a striatal-enriched small G protein, mediates mTOR signaling and L-DOPA-induced dyskinesia. Nat Neurosci 15(2):191–193
pubmed: 22179112
pmcid: 3267880
doi: 10.1038/nn.2994
Eshragi M et al. (2019) RasGRP1 is a Causal Factor in the Development of L-DOPA-induced dyskinesia in Parkinson Disease. Sci Adv In press
Subramaniam S et al (2009) Rhes, a striatal specific protein, mediates mutant-huntingtin cytotoxicity. Science 324(5932):1327–1330
pubmed: 19498170
pmcid: 2745286
doi: 10.1126/science.1172871
Ramirez-Jarquin UN et al (2022) Deletion of SUMO1 attenuates behavioral and anatomical deficits by regulating autophagic activities in Huntington disease. Proc Natl Acad Sci U S A 119:5
doi: 10.1073/pnas.2107187119
Ehrenberg AJ et al (2021) Patterns of neuronal Rhes as a novel hallmark of tauopathies. Acta Neuropathol 141(5):651–666
pubmed: 33677647
pmcid: 8418783
doi: 10.1007/s00401-021-02279-2
Hernandez I et al (2019) A farnesyltransferase inhibitor activates lysosomes and reduces tau pathology in mice with tauopathy. Sci Transl Med 11:485
doi: 10.1126/scitranslmed.aat3005
Liu YL et al (2008) RASD2, MYH9, and CACNG2 genes at chromosome 22q12 associated with the subgroup of schizophrenia with non-deficit in sustained attention and executive function. Biol Psychiatry 64(9):789–796
pubmed: 18571626
doi: 10.1016/j.biopsych.2008.04.035
Vitucci D et al (2016) Rasd2 Modulates Prefronto-Striatal Phenotypes in Humans and “Schizophrenia-Like Behaviors” in Mice. Neuropsychopharmacology 41(3):916–927
pubmed: 26228524
doi: 10.1038/npp.2015.228
Vadgama N et al (2019) De novo single-nucleotide and copy number variation in discordant monozygotic twins reveals disease-related genes. Eur J Hum Genet 27(7):1121–1133
pubmed: 30886340
pmcid: 6777616
doi: 10.1038/s41431-019-0376-7
Sharma M, Subramaniam S (2019) Rhes travels from cell to cell and transports Huntington disease protein via TNT-like protrusion. J Cell Biol 218(6):1972–1993
pubmed: 31076452
pmcid: 6548131
doi: 10.1083/jcb.201807068
Ramirez-Jarquin UN et al (2022) Rhes protein transits from neuron to neuron and facilitates mutant huntingtin spreading in the brain. Sci Adv 8(12):eabm3877
pubmed: 35319973
pmcid: 8942366
doi: 10.1126/sciadv.abm3877
Subramaniam S (2020) Rhes Tunnels: A Radical New Way of Communication in the Brain’s Striatum? BioEssays 42(6):e1900231
pubmed: 32236969
pmcid: 7310467
doi: 10.1002/bies.201900231
Chapple CE et al (2015) Extreme multifunctional proteins identified from a human protein interaction network. Nat Commun 6:7412
pubmed: 26054620
doi: 10.1038/ncomms8412
Issaeva N (2019) p53 Signaling in Cancers. Cancers (Basel) 11:3
doi: 10.3390/cancers11030332
Santucci R et al (2019) Cytochrome c: An extreme multifunctional protein with a key role in cell fate. Int J Biol Macromol 136:1237–1246
pubmed: 31252007
doi: 10.1016/j.ijbiomac.2019.06.180
Subramaniam S et al (2010) Rhes, a physiologic regulator of sumoylation, enhances cross-sumoylation between the basic sumoylation enzymes E1 and Ubc9. J Biol Chem 285(27):20428–20432
pubmed: 20424159
pmcid: 2898300
doi: 10.1074/jbc.C110.127191
Mealer RG et al (2014) Rhes, a striatal-selective protein implicated in Huntington disease, binds beclin-1 and activates autophagy. J Biol Chem 289(6):3547–3554
pubmed: 24324270
doi: 10.1074/jbc.M113.536912
Galisson F et al (2011) A novel proteomics approach to identify SUMOylated proteins and their modification sites in human cells. Mol Cell Proteomics 10(2):M110-004796
doi: 10.1074/mcp.M110.004796
Lamoliatte F et al (2013) Targeted identification of SUMOylation sites in human proteins using affinity enrichment and paralog-specific reporter ions. Mol Cell Proteomics 12(9):2536–2550
pubmed: 23750026
pmcid: 3769329
doi: 10.1074/mcp.M112.025569
Tammsalu T et al (2015) Proteome-wide identification of SUMO modification sites by mass spectrometry. Nat Protoc 10(9):1374–1388
pubmed: 26292070
doi: 10.1038/nprot.2015.095
Lamoliatte F et al (2014) Large-scale analysis of lysine SUMOylation by SUMO remnant immunoaffinity profiling. Nat Commun 5:5409
pubmed: 25391492
doi: 10.1038/ncomms6409
Lamoliatte F et al (2017) Uncovering the SUMOylation and ubiquitylation crosstalk in human cells using sequential peptide immunopurification. Nat Commun 8:14109
pubmed: 28098164
pmcid: 5253644
doi: 10.1038/ncomms14109
Li C et al (2020) Quantitative SUMO proteomics identifies PIAS1 substrates involved in cell migration and motility. Nat Commun 11(1):834
pubmed: 32047143
pmcid: 7012886
doi: 10.1038/s41467-020-14581-w
McManus FP et al (2018) Quantitative SUMO proteomics reveals the modulation of several PML nuclear body associated proteins and an anti-senescence function of UBC9. Sci Rep 8(1):7754
pubmed: 29773808
pmcid: 5958138
doi: 10.1038/s41598-018-25150-z
Swarnkar S et al (2015) Ectopic expression of the striatal-enriched GTPase Rhes elicits cerebellar degeneration and an ataxia phenotype in Huntington’s disease. Neurobiol Dis 82:66–77
pubmed: 26048156
doi: 10.1016/j.nbd.2015.05.011
Krämer A et al (2014) Causal analysis approaches in Ingenuity Pathway Analysis. Bioinformatics 30(4):523–530
pubmed: 24336805
doi: 10.1093/bioinformatics/btt703
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(12):1367–1372
pubmed: 19029910
doi: 10.1038/nbt.1511
Rabellino A, Andreani C, Scaglioni PP (2017) The Role of PIAS SUMO E3-Ligases in Cancer. Cancer Res 77(7):1542–1547
pubmed: 28330929
pmcid: 5380518
doi: 10.1158/0008-5472.CAN-16-2958
Bouchard D et al (2021) SUMO paralogue-specific functions revealed through systematic analysis of human knockout cell lines and gene expression data. Mol Biol Cell 32(19):1849–1866
McManus FP, Lamoliatte F, Thibault P (2017) Identification of cross talk between SUMOylation and ubiquitylation using a sequential peptide immunopurification approach. Nat Protoc 12(11):2342–2358
pubmed: 29048423
doi: 10.1038/nprot.2017.105
Nguyen HB, QLA (2012) Encyclopedia of Signaling Molecules. Springer, New York, NY
Caron E (2003) Cellular functions of the Rap1 GTP-binding protein: a pattern emerges. J Cell Sci 116(Pt 3):435–440
pubmed: 12508104
doi: 10.1242/jcs.00238
Jia Y et al (2019) Chemical Tools and Biochemical Assays for SUMO Specific Proteases (SENPs). ACS Chem Biol 14(11):2389–2395
pubmed: 31361113
pmcid: 6862319
doi: 10.1021/acschembio.9b00402
Fuhs SR, Insel PA (2011) Caveolin-3 undergoes SUMOylation by the SUMO E3 ligase PIASy: sumoylation affects G-protein-coupled receptor desensitization. J Biol Chem 286(17):14830–14841
pubmed: 21362625
pmcid: 3083237
doi: 10.1074/jbc.M110.214270
Krumova P et al (2011) Sumoylation inhibits alpha-synuclein aggregation and toxicity. J Cell Biol 194(1):49–60
pubmed: 21746851
pmcid: 3135405
doi: 10.1083/jcb.201010117
Nathan D et al (2006) Histone sumoylation is a negative regulator in Saccharomyces cerevisiae and shows dynamic interplay with positive-acting histone modifications. Genes Dev 20(8):966–976
pubmed: 16598039
pmcid: 1472304
doi: 10.1101/gad.1404206
Geiss-Friedlander R, Melchior F (2007) Concepts in sumoylation: a decade on. Nat Rev Mol Cell Biol 8(12):947–956
pubmed: 18000527
doi: 10.1038/nrm2293
Quach DH et al (2013) A sympathetic neuron autonomous role for Egr3-mediated gene regulation in dendrite morphogenesis and target tissue innervation. J Neurosci 33(10):4570–4583
pubmed: 23467373
pmcid: 3710710
doi: 10.1523/JNEUROSCI.5481-12.2013
Kuwajima T, Nishimura I, Yoshikawa K (2006) Necdin promotes GABAergic neuron differentiation in cooperation with Dlx homeodomain proteins. J Neurosci 26(20):5383–5392
pubmed: 16707790
pmcid: 6675313
doi: 10.1523/JNEUROSCI.1262-06.2006
Heikamp EB et al (2014) The AGC kinase SGK1 regulates TH1 and TH2 differentiation downstream of the mTORC2 complex. Nat Immunol 15(5):457–464
pubmed: 24705297
pmcid: 4267697
doi: 10.1038/ni.2867
Lejard V et al (2011) EGR1 and EGR2 involvement in vertebrate tendon differentiation. J Biol Chem 286(7):5855–5867
pubmed: 21173153
doi: 10.1074/jbc.M110.153106
Yamauchi K et al (2017) Netrin-1 Derived from the Ventricular Zone, but not the Floor Plate, Directs Hindbrain Commissural Axons to the Ventral Midline. Sci Rep 7(1):11992
pubmed: 28931893
pmcid: 5607380
doi: 10.1038/s41598-017-12269-8
Fantin A, Maden CH, Ruhrberg C (2009) Neuropilin ligands in vascular and neuronal patterning. Biochem Soc Trans 37(Pt 6):1228–1232
pubmed: 19909252
pmcid: 3512079
doi: 10.1042/BST0371228
Das G et al (2016) EphA5 and EphA6: regulation of neuronal and spine morphology. Cell Biosci 6:48
pubmed: 27489614
pmcid: 4971699
doi: 10.1186/s13578-016-0115-5
Dennis DJ, Han S, Schuurmans C (2019) bHLH transcription factors in neural development, disease, and reprogramming. Brain Res 1705:48–65
pubmed: 29544733
doi: 10.1016/j.brainres.2018.03.013
Li H et al (2008) Transcription factor MEF2C influences neural stem/progenitor cell differentiation and maturation in vivo. Proc Natl Acad Sci U S A 105(27):9397–9402
pubmed: 18599437
pmcid: 2453715
doi: 10.1073/pnas.0802876105
Ozdinler PH, Erzurumlu RS (2002) Slit2, a branching-arborization factor for sensory axons in the Mammalian CNS. J Neurosci 22(11):4540–4549
pubmed: 12040061
pmcid: 4260804
doi: 10.1523/JNEUROSCI.22-11-04540.2002
Sun L et al (2013) PIASy mediates hypoxia-induced SIRT1 transcriptional repression and epithelial-to-mesenchymal transition in ovarian cancer cells. J Cell Sci 126(Pt 17):3939–3947
pubmed: 23843607
Yan C et al (2016) Protein Inhibitor of Activated STAT Y (PIASy) Regulates Insulin Secretion by Interacting with LIM Homeodomain Transcription Factor Isl1. Sci Rep 6:39308
pubmed: 28000708
pmcid: 5175275
doi: 10.1038/srep39308
Chowdhury B et al (2016) PBRM1 Regulates the Expression of Genes Involved in Metabolism and Cell Adhesion in Renal Clear Cell Carcinoma. PLoS ONE 11(4):e0153718
pubmed: 27100670
pmcid: 4839679
doi: 10.1371/journal.pone.0153718
West KO et al (2019) The Splicing Factor hnRNP M Is a Critical Regulator of Innate Immune Gene Expression in Macrophages. Cell Rep 29(6):1594–1609
pubmed: 31693898
pmcid: 6981299
doi: 10.1016/j.celrep.2019.09.078
Zupkovitz G et al (2006) Negative and positive regulation of gene expression by mouse histone deacetylase 1. Mol Cell Biol 26(21):7913–7928
pubmed: 16940178
pmcid: 1636735
doi: 10.1128/MCB.01220-06
Greer CB et al (2015) Histone Deacetylases Positively Regulate Transcription through the Elongation Machinery. Cell Rep 13(7):1444–1455
pubmed: 26549458
pmcid: 4934896
doi: 10.1016/j.celrep.2015.10.013
Sharma M et al (2019) Rhes, a striatal-enriched protein, promotes mitophagy via Nix. Proc Natl Acad Sci U S A 116(47):23760–23771
pubmed: 31676548
pmcid: 6876193
doi: 10.1073/pnas.1912868116
Spano D et al (2004) Rhes is involved in striatal function. Mol Cell Biol 24(13):5788–5796
pubmed: 15199135
pmcid: 480889
doi: 10.1128/MCB.24.13.5788-5796.2004
Hickey CM, Wilson NR, Hochstrasser M (2012) Function and regulation of SUMO proteases. Nat Rev Mol Cell Biol 13(12):755–766
pubmed: 23175280
pmcid: 3668692
doi: 10.1038/nrm3478
Hecker CM et al (2006) Specification of SUMO1- and SUMO2-interacting motifs. J Biol Chem 281(23):16117–16127
pubmed: 16524884
doi: 10.1074/jbc.M512757200
Kumar R et al (2017) The STUbL RNF4 regulates protein group SUMOylation by targeting the SUMO conjugation machinery. Nat Commun 8(1):1809
pubmed: 29180619
pmcid: 5703878
doi: 10.1038/s41467-017-01900-x
Hendriks IA et al (2014) Uncovering global SUMOylation signaling networks in a site-specific manner. Nat Struct Mol Biol 21(10):927–936
pubmed: 25218447
pmcid: 4259010
doi: 10.1038/nsmb.2890
Ciobanu DC et al (2010) Detection, validation, and downstream analysis of allelic variation in gene expression. Genetics 184(1):119–128
pubmed: 19884314
pmcid: 2802080
doi: 10.1534/genetics.109.107474
Liu HW et al (2012) Chromatin modification by SUMO-1 stimulates the promoters of translation machinery genes. Nucleic Acids Res 40(20):10172–10186
pubmed: 22941651
pmcid: 3488252
doi: 10.1093/nar/gks819
Rosonina E et al (2017) Regulation of transcription factors by sumoylation. Transcription 8(4):220–231
pubmed: 28379052
pmcid: 5574528
doi: 10.1080/21541264.2017.1311829
David G, Neptune MA, DePinho RA (2002) SUMO-1 modification of histone deacetylase 1 (HDAC1) modulates its biological activities. J Biol Chem 277(26):23658–23663
pubmed: 11960997
doi: 10.1074/jbc.M203690200
Joung H et al (2018) Sumoylation of histone deacetylase 1 regulates MyoD signaling during myogenesis. Exp Mol Med 50(1):e427
pubmed: 29328071
pmcid: 5799798
doi: 10.1038/emm.2017.236
Tao CC et al (2017) Epigenetic regulation of HDAC1 SUMOylation as an endogenous neuroprotection against Abeta toxicity in a mouse model of Alzheimer’s disease. Cell Death Differ 24(4):597–614
pubmed: 28186506
pmcid: 5384022
doi: 10.1038/cdd.2016.161
Zhang R, Mehla R, Chauhan A (2010) Perturbation of host nuclear membrane component RanBP2 impairs the nuclear import of human immunodeficiency virus -1 preintegration complex (DNA). PLoS ONE 5(12):e15620
pubmed: 21179483
pmcid: 3001881
doi: 10.1371/journal.pone.0015620
Turpin P, Ossareh-Nazari B, Dargemont C (1999) Nuclear transport and transcriptional regulation. FEBS Lett 452(1–2):82–86
pubmed: 10376683
doi: 10.1016/S0014-5793(99)00533-5
Vassileva MT, Matunis MJ (2004) SUMO modification of heterogeneous nuclear ribonucleoproteins. Mol Cell Biol 24(9):3623–3632
pubmed: 15082759
pmcid: 387737
doi: 10.1128/MCB.24.9.3623-3632.2004
Kirsh O et al (2002) The SUMO E3 ligase RanBP2 promotes modification of the HDAC4 deacetylase. EMBO J 21(11):2682–2691
pubmed: 12032081
pmcid: 125385
doi: 10.1093/emboj/21.11.2682
Pozzi B et al (2017) SUMO conjugation to spliceosomal proteins is required for efficient pre-mRNA splicing. Nucleic Acids Res 45(11):6729–6745
pubmed: 28379520
pmcid: 5499870
doi: 10.1093/nar/gkx213
Laplante M, Sabatini DM (2013) Regulation of mTORC1 and its impact on gene expression at a glance. J Cell Sci 126(Pt 8):1713–1719
pubmed: 23641065
pmcid: 3678406
Kunkel J, Luo X, Capaldi AP (2019) Integrated TORC1 and PKA signaling control the temporal activation of glucose-induced gene expression in yeast. Nat Commun 10(1):3558
pubmed: 31395866
pmcid: 6687784
doi: 10.1038/s41467-019-11540-y
Yapo C et al (2018) Switch-like PKA responses in the nucleus of striatal neurons. J Cell Sci 131:14
Carbo M et al (2019) Bioinformatics analysis of Ras homologue enriched in the striatum, a potential target for Huntington’s disease therapy. Int J Mol Med 44(6):2223–2233
pubmed: 31638189
pmcid: 6844632
Gasset-Rosa F et al (2017) Polyglutamine-Expanded Huntingtin Exacerbates Age-Related Disruption of Nuclear Integrity and Nucleocytoplasmic Transport. Neuron 94(1):48–57
pubmed: 28384474
pmcid: 5479704
doi: 10.1016/j.neuron.2017.03.027
Grima JC et al (2017) Mutant Huntingtin Disrupts the Nuclear Pore Complex. Neuron 94(1):93–107
pubmed: 28384479
pmcid: 5595097
doi: 10.1016/j.neuron.2017.03.023
Cornett J et al (2005) Polyglutamine expansion of huntingtin impairs its nuclear export. Nat Genet 37(2):198–204
pubmed: 15654337
doi: 10.1038/ng1503
Ritterhoff T et al (2016) The RanBP2/RanGAP1*SUMO1/Ubc9 SUMO E3 ligase is a disassembly machine for Crm1-dependent nuclear export complexes. Nat Commun 7:11482
pubmed: 27160050
pmcid: 4866044
doi: 10.1038/ncomms11482