https://doi.org/10.4081/ejh.2021.3241
Super-resolution study of PIAS SUMO E3-ligases in hippocampal and cortical neurons
Submitted: 24 March 2021
Accepted: 22 July 2021
Published: 11 August 2021
Accepted: 22 July 2021
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The SUMOylation machinery is a regulator of neuronal activity and synaptic plasticity. It is composed of SUMO isoforms and specialized enzymes named E1, E2 and E3 SUMO ligases. Recent studies have highlighted how SUMO isoforms and E2 enzymes localize with synaptic markers to support previous functional studies but less information is available on E3 ligases. PIAS proteins - belonging to the protein inhibitor of activated STAT (PIAS) SUMO E3-ligase family - are the best-characterized SUMO E3-ligases and have been linked to the formation of spatial memory in rodents. Whether however they exert their function co-localizing with synaptic markers is still unclear. In this study, we applied for the first time structured illumination microscopy (SIM) to PIAS ligases to investigate the co-localization of PIAS1 and PIAS3 with synaptic markers in hippocampal and cortical murine neurons. The results indicate partial co-localization of PIAS1 and PIAS3 with synaptic markers in hippocampal neurons and much rarer occurrence in cortical neurons. This is in line with previous super-resolution reports describing the co-localization with synaptic markers of other components of the SUMOylation machinery.
Routtenberg A, Rekart JL. Post-translational protein modification as the substrate for long-lasting memory. Trends Neurosci 2005;28:12–9.
DOI: https://doi.org/10.1016/j.tins.2004.11.006
Tak I-R, Ali F, Dar JS, Magray AR, Ganai BA, Chishti MZ. Chapter 1 - Posttranslational modifications of proteins and their role in biological processes and associated diseases. In: Dar TA, Singh LR, editors. Protein Modificomics. Academic Press; 2019. p. 1-35.
Kerscher O. SUMO junction-what’s your function? New insights through SUMO-interacting motifs. EMBO Rep 2007;8:550–5.
DOI: https://doi.org/10.1038/sj.embor.7400980
Marcelli S, Ficulle E, Iannuzzi F, Kövari E, Nisticò R, Feligioni M. Targeting SUMO-1ylation contrasts synaptic dysfunction in a mouse model of Alzheimer’s Disease. Mol Neurobiol 2017;54:6609–23.
DOI: https://doi.org/10.1007/s12035-016-0176-9
Schorova L, Pronot M, Poupon G, Prieto M, Folci A, Khayachi A, et al. The synaptic balance between sumoylation and desumoylation is maintained by the activation of metabotropic mGlu5 receptors. Cell Mol Life Sci 2019;76:3019–31.
DOI: https://doi.org/10.1007/s00018-019-03075-8
Henley JM, Seager R, Nakamura Y, Talandyte K, Nair J, Wilkinson KA. SUMOylation of synaptic and synapse-associated proteins: An update. J Neurochem 2021;156:145-61.
DOI: https://doi.org/10.1111/jnc.15103
Schorova L, Martin S. Sumoylation in synaptic function and dysfunction. Front Synaptic Neurosci 2016;8:9.
DOI: https://doi.org/10.3389/fnsyn.2016.00009
Lee L, Sakurai M, Matsuzaki S, Arancio O, Fraser P. SUMO and Alzheimer’s disease. Neuromolecular Med 2013;15:720–36.
DOI: https://doi.org/10.1007/s12017-013-8257-7
Eckermann K. SUMO and Parkinson’s disease. Neuromolecular Med 2013;15:737–59.
DOI: https://doi.org/10.1007/s12017-013-8259-5
Guerra de Souza AC, Prediger RD, Cimarosti H. SUMO-regulated mitochondrial function in Parkinson’s disease. J Neurochem 2016;137:673–86.
DOI: https://doi.org/10.1111/jnc.13599
Gareau JR, Lima CD. The SUMO pathway: emerging mechanisms that shape specificity, conjugation and recognition. Nat Rev Mol Cell Biol 2010;11:861–71.
DOI: https://doi.org/10.1038/nrm3011
Bohren KM, Nadkarni V, Song JH, Gabbay KH, Owerbach D. A M55V polymorphism in a novel SUMO gene (SUMO-4) differentially activates heat shock transcription factors and is associated with susceptibility to type I diabetes mellitus. J Biol Chem 2004;279:27233–8.
DOI: https://doi.org/10.1074/jbc.M402273200
Henley JM, Craig TJ, Wilkinson KA. Neuronal SUMOylation: Mechanisms, physiology, and roles in neuronal dysfunction. Physiol Rev 2014;94:1249–85.
DOI: https://doi.org/10.1152/physrev.00008.2014
Gareau JR, Reverter D, Lima CD. Determinants of small ubiquitin-like modifier 1 (SUMO1) protein specificity, E3 ligase, and SUMO-RanGAP1 binding activities of nucleoporin RanBP2. J Biol Chem 2012;287:4740–51.
DOI: https://doi.org/10.1074/jbc.M111.321141
Wilkinson KA, Nakamura Y, Henley JM. Targets and consequences of protein SUMOylation in neurons. Brain Res Rev 2010;64:195–212.
DOI: https://doi.org/10.1016/j.brainresrev.2010.04.002
Rabellino A, Andreani C, Scaglioni PP. The role of PIAS SUMO E3-ligases in cancer. Cancer Res 2017;77:1542–7.
DOI: https://doi.org/10.1158/0008-5472.CAN-16-2958
ScienceDirect Topics [Internet]. Ubiquitin Protein Ligase E3 - an overview. Accessed: 2020 Dec 24. Available from: https://www.sciencedirect.com/topics/medicine-and-dentistry/ubiquitin-protein-ligase-e3
Yang W-S, Campbell M, Kung H-J, Chang P-C. In vitro SUMOylation assay to study SUMO E3 ligase activity. J Vis Exp 2018;131:56629.
Kunz K, Piller T, Müller S. SUMO-specific proteases and isopeptidases of the SENP family at a glance. J Cell Sci 2018;131:jcs211904.
Martin S, Nishimune A, Mellor JR, Henley JM. SUMOylation regulates kainate-receptor-mediated synaptic transmission. Nature 2007;447:321–5.
DOI: https://doi.org/10.1038/nature05736
Loriol C, Khayachi A, Poupon G, Gwizdek C, Martin S. Activity-dependent regulation of the sumoylation machinery in rat hippocampal neurons. Biol Cell 2013;105:30–45.
DOI: https://doi.org/10.1111/boc.201200016
Ficulle E, Sufian MDS, Tinelli C, Corbo M, Feligioni M. Aging-related SUMOylation pattern in the cortex and blood plasma of wild type mice. Neurosci Lett 2018;668:48–54.
DOI: https://doi.org/10.1016/j.neulet.2018.01.004
Castro-Gomez S, Barrera-Ocampo A, Machado-Rodriguez G, Castro-Alvarez JF, Glatzel M, Giraldo M, et al. Specific de-SUMOylation triggered by acquisition of spatial learning is related to epigenetic changes in the rat hippocampus. Neuroreport 2013;24:976–81.
DOI: https://doi.org/10.1097/WNR.0000000000000025
Daniel JA, Cooper BH, Palvimo JJ, Zhang F-P, Brose N, Tirard M. Analysis of SUMO1-conjugation at synapses. eLif. 2017;6:e26338.
Daniel JA, Cooper BH, Palvimo JJ, Zhang F-P, Brose N, Tirard M. Response: Commentary: Analysis of SUMO1-conjugation at synapses. Front Cell Neurosci 2018;12:117.
DOI: https://doi.org/10.3389/fncel.2018.00117
Colnaghi L, Russo L, Natale C, Restelli E, Cagnotto A, Salmona M, et al. Super resolution microscopy of SUMO proteins in neurons. Front Cell Neurosci 2019;13:486.
DOI: https://doi.org/10.3389/fncel.2019.00486
Colnaghi L, Conz A, Russo L, Musi CA, Fioriti L, Borsello T, et al. Neuronal localization of SENP proteins with super resolution microscopy. Brain Sci 2020;10:778.
DOI: https://doi.org/10.3390/brainsci10110778
Russo L, Natale C, Conz A, Kelk J, Restelli E, Chiesa R, et al. Super-resolution imaging to study co-localization of proteins and synaptic markers in primary neurons. J Vis Exp 2020;164:e61434.
Silveirinha VC, Lin H, Tanifuji S, Mochida S, Cottrell GS, Cimarosti H, et al. CaV2.2 (N-type) voltage-gated calcium channels are activated by SUMOylation pathways. Cell Calcium 2021;93:102326.
DOI: https://doi.org/10.1016/j.ceca.2020.102326
Chung CD, Liao J, Liu B, Rao X, Jay P, Berta P, et al. Specific inhibition of Stat3 signal transduction by PIAS3. Science 1997;278:1803–5.
DOI: https://doi.org/10.1126/science.278.5344.1803
Liu B, Liao J, Rao X, Kushner SA, Chung CD, Chang DD, et al. Inhibition of Stat1-mediated gene activation by PIAS1. Proc Natl Acad Sci USA 1998;95:10626–31.
DOI: https://doi.org/10.1073/pnas.95.18.10626
Tai DJC, Hsu WL, Liu YC, Ma YL, Lee EHY. Novel role and mechanism of protein inhibitor of activated STAT1 in spatial learning. EMBO J 2011;30:205–20.
DOI: https://doi.org/10.1038/emboj.2010.290
Liu SY, Ma YL, Lee EHY. NMDA receptor signaling mediates the expression of protein inhibitor of activated STAT1 (PIAS1) in rat hippocampus. Neuropharmacology 2013;65:101-13.
DOI: https://doi.org/10.1016/j.neuropharm.2012.08.024
Chen Y-C, Hsu W-L, Ma Y-L, Tai DJC, Lee EHY. CREB SUMOylation by the E3 ligase PIAS1 enhances spatial memory. J Neurosci Off J Soc Neurosci 2014;34:9574–89.
DOI: https://doi.org/10.1523/JNEUROSCI.4302-13.2014
Du C-P, Wang M, Geng C, Hu B, Meng L, Xu Y, et al. Activity-induced SUMOylation of neuronal nitric oxide synthase is associated with plasticity of synaptic transmission and extracellular signal-regulated kinase 1/2 signaling. Antioxid Redox Signal 2020;32:18–34.
DOI: https://doi.org/10.1089/ars.2018.7669
Ghosh H, Auguadri L, Battaglia S, Simone Thirouin Z, Zemoura K, Messner S, et al. Several posttranslational modifications act in concert to regulate gephyrin scaffolding and GABAergic transmission. Nat Commun 2016;7:13365.
DOI: https://doi.org/10.1038/ncomms13365
Chiba T, Yamada M, Sasabe J, Terashita K, Shimoda M, Matsuoka M, et al. Amyloid-β causes memory impairment by disturbing the JAK2/STAT3 axis in hippocampal neurons. Mol Psychiatry 2009;14:206–22.
DOI: https://doi.org/10.1038/mp.2008.105
Liu S-Y, Ma Y-L, Hsu W-L, Chiou H-Y, Lee EHY. Protein inhibitor of activated STAT1 Ser503 phosphorylation-mediated Elk-1 SUMOylation promotes neuronal survival in APP/PS1 mice. Br J Pharmacol 2019;176:1793–810.
DOI: https://doi.org/10.1111/bph.14656
O’Rourke JG, Gareau JR, Ochaba J, Song W, Raskó T, Reverter D, et al. SUMO-2 and PIAS1 modulate insoluble mutant huntingtin protein accumulation. Cell Rep 2013;4:362–75.
DOI: https://doi.org/10.1016/j.celrep.2013.06.034
Morozko EL, Smith-Geater C, Monteys AM, Pradhan S, Lim RG, Langfelder P, et al. PIAS1 modulates striatal transcription, DNA damage repair, and SUMOylation with relevance to Huntington’s disease. Proc Natl Acad Sci USA 2021;118:e2021836118.
Rubio MD, Wood K, Haroutunian V, Meador-Woodruff JH. Dysfunction of the ubiquitin proteasome and ubiquitin-like systems in schizophrenia. Neuropsychopharmacology 2013;38:1910–20.
DOI: https://doi.org/10.1038/npp.2013.84
Huang Z, Fujiwara K, Minamide R, Hasegawa K, Yoshikawa K. Necdin controls proliferation and apoptosis of embryonic neural stem cells in an oxygen tension-dependent manner. J Neurosci Off J Soc Neurosci 2013;33:10362–73.
DOI: https://doi.org/10.1523/JNEUROSCI.5682-12.2013
Lin H-Y, Liu Y-S, Huang C-Y, Cathomas F, Liu K, Wang J, et al. SUMO E3 ligase PIAS1 is a potential biomarker indicating stress susceptibility. Psychoneuroendocrinology 2020;120:104800.
DOI: https://doi.org/10.1016/j.psyneuen.2020.104800
Floriou-Servou A, von Ziegler L, Stalder L, Sturman O, Privitera M, Rassi A, et al. Distinct proteomic, transcriptomic, and epigenetic stress responses in dorsal and ventral hippocampus. Biol Psychiatry 2018;84:531–41.
DOI: https://doi.org/10.1016/j.biopsych.2018.02.003
Cordelieres FP, Bolte S. JACoP v2.0: improving the user experience with co-localization studies. Available from: https://imagejdocu.tudor.lu/_media/plugin/analysis/jacop_2.0/just_another_colocalization_plugin/jacop_ijconf2008.pdf
Wiedenmann B, Franke WW. Identification and localization of synaptophysin, an integral membrane glycoprotein of Mr 38,000 characteristic of presynaptic vesicles. Cell 1985;41:1017–28.
DOI: https://doi.org/10.1016/S0092-8674(85)80082-9
Chen X, Winters C, Crocker V, Lazarou M, Sousa AA, Leapman RD, et al. Identification of PSD-95 in the postsynaptic density using miniSOG and EM tomography. Front Neuroanat 2018;12:107.
DOI: https://doi.org/10.3389/fnana.2018.00107
Dunn KW, Kamocka MM, McDonald JH. A practical guide to evaluating colocalization in biological microscopy. Am J Physiol Cell Physiol 2011;300:C723-42.
Huang B, Bates M, Zhuang X. Super-resolution fluorescence microscopy. Annu Rev Biochem 2009;78:993-1016.
DOI: https://doi.org/10.1146/annurev.biochem.77.061906.092014
Igarashi M, Nozumi M, Wu L-G, Zanacchi FC, Katona I, Barna L, et al. New observations in neuroscience using superresolution microscopy. J Neurosci 2018;38:9459–67.
DOI: https://doi.org/10.1523/JNEUROSCI.1678-18.2018
Schikorski T, Stevens CF. Quantitative ultrastructural analysis of hippocampal excitatory synapses. J Neurosci 1997;17:5858–67.
DOI: https://doi.org/10.1523/JNEUROSCI.17-15-05858.1997
Wasik U, Filipek A. Non-nuclear function of sumoylated proteins. Biochim Biophys Acta 2014;1843:2878–85.
DOI: https://doi.org/10.1016/j.bbamcr.2014.07.018
Adler J, Parmryd I. Quantifying colocalization by correlation: The Pearson correlation coefficient is superior to the Mander’s overlap coefficient. Cytometry A 2010;77:733–42.
DOI: https://doi.org/10.1002/cyto.a.20896
Dabir S, Kluge A, Dowlati A. The association and nuclear translocation of the PIAS3-STAT3 complex is ligand and time dependent. Mol Cancer Res 2009;7:1854–60.
DOI: https://doi.org/10.1158/1541-7786.MCR-09-0313
Hsu W-L, Ma Y-L, Hsieh D-Y, Liu Y-C, Lee EH. STAT1 negatively regulates spatial memory formation and mediates the memory-impairing effect of Aβ. Neuropsychopharmacology 2014;39:746–58.
DOI: https://doi.org/10.1038/npp.2013.263
Mizuno M, Yamada K, Maekawa N, Saito K, Seishima M, Nabeshima T. CREB phosphorylation as a molecular marker of memory processing in the hippocampus for spatial learning. Behav Brain Res 2002;133:135–41.
DOI: https://doi.org/10.1016/S0166-4328(01)00470-3
Viola H, Furman M, Izquierdo LA, Alonso M, Barros DM, de Souza MM, et al. Phosphorylated cAMP response element-binding protein as a molecular marker of memory processing in rat hippocampus: effect of novelty. J Neurosci 2000;20:RC112.
Silva AJ, Kogan JH, Frankland PW, Kida S. CREB and memory. Annu Rev Neurosci 1998;21:127–48.
DOI: https://doi.org/10.1146/annurev.neuro.21.1.127
Kandel ER. The molecular biology of memory: cAMP, PKA, CRE, CREB-1, CREB-2, and CPEB. Mol Brain 2012;5:14.
DOI: https://doi.org/10.1186/1756-6606-5-14
Steffan JS, Agrawal N, Pallos J, Rockabrand E, Trotman LC, Slepko N, et al. SUMO modification of Huntingtin and Huntington’s disease pathology. Science 2004;304:100–4.
DOI: https://doi.org/10.1126/science.1092194
Tai DJC, Liu YC, Hsu WL, Ma YL, Cheng SJ, Liu SY, et al. MeCP2 SUMOylation rescues Mecp2-mutant-induced behavioural deficits in a mouse model of Rett syndrome. Nat Commun 2016;7:10552.
DOI: https://doi.org/10.1038/ncomms10552
Zanella CA, Tasca CI, Henley JM, Wilkinson KA, Cimarosti HI. Guanosine modulates SUMO2/3-ylation in neurons and astrocytes via adenosine receptors. Purinergic Signal 2020;16:439–50.
DOI: https://doi.org/10.1007/s11302-020-09723-0
Wang L, Rodriguiz RM, Wetsel WC, Sheng H, Zhao S, Liu X, et al. Neuron-specific Sumo1–3 knockdown in mice impairs episodic and fear memories. J Psychiatry Neurosci 2014;39:259-66.
DOI: https://doi.org/10.1503/jpn.130148
Supporting Agencies
This work was supported by Brightfocus Grant A2019296F and a grant from the Fondo di Beneficenza-Gruppo Intesa Sanpaolo to L.C.How to Cite
Conz, A., Musi, C. A., Russo, L., Borsello, T., & Colnaghi, L. (2021). Super-resolution study of PIAS SUMO E3-ligases in hippocampal and cortical neurons. European Journal of Histochemistry, 65(s1). https://doi.org/10.4081/ejh.2021.3241
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