title: CREB SUMOylation by the E3 ligase PIAS1 enhances spatial memory.
abstract: cAMP-responsive element binding protein (CREB) phosphorylation and signaling plays an important role in long-term memory formation, but other posttranslational modifications of CREB are less known. Here, we found that CREB1Δ, the short isoform of CREB, could be sumoylated by the small ubiquitin-like modifier (SUMO) E3 ligase protein inhibitor of activated STAT1 (PIAS1) at Lys271 and Lys290 and PIAS1 SUMOylation of CREB1Δ increased the expression level of CREB1Δ. CREB1Δ could also be sumoylated by other PIAS family proteins, but not by the E3 ligases RanBP2 and Pc2 or by the E2 ligase Ubc9. Furthermore, water maze training increased the level of endogenous CREB SUMOylation in rat CA1 neurons determined by in vitro SUMOylation assay, but this effect was not observed in other brain areas. Moreover, transduction of Lenti-CREBWT to rat CA1 area facilitated, whereas transduction of Lenti-CREB double sumo-mutant (CREBK271RK290R) impaired, spatial learning and memory performance. Transduction of Lenti-CREBWT-SUMO1 fusion vector to rat CA1 area showed a more significant effect in enhancing spatial learning and memory and CREB SUMOylation. Lenti-CREBWT transduction increased, whereas Lenti-CREBK271RK290R transduction decreased, CREB DNA binding to the brain-derived neurotrophic factor (bdnf) promoter and decreased bdnf mRNA expression. Knock-down of PIAS1 expression in CA1 area by PIAS1 siRNA transfection impaired spatial learning and memory and decreased endogenous CREB SUMOylation. In addition, CREB SUMOylation was CREB phosphorylation dependent and lasted longer. Therefore, CREB phosphorylation may be responsible for signal transduction during the early phase of long-term memory formation, whereas CREB SUMOylation sustains long-term memory.
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, and.
authors.forename: Yan-Chu
authors.initials: YC
authors.lastname: Chen
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan, Republic of China.
authors.forename: Wei-Lun
authors.initials: WL
authors.lastname: Hsu
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan, Republic of China.
authors.forename: Yun-Li
authors.initials: YL
authors.lastname: Ma
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan, Republic of China.
authors.forename: Derek J C
authors.initials: DJ
authors.lastname: Tai
authors.affiliation: Graduate Institute of Life Sciences, National Defense Medical Center, and Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan, Republic of China eminy@gate.sinica.edu.tw.
authors.forename: Eminy H Y
authors.initials: EH
authors.lastname: Lee
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D011485:Protein Binding / Q000235:genetics; D050828:Protein Inhibitors of Activated STAT / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000235:genetics; D013028:Space Perception / Q000502:physiology*; D058207:Sumoylation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D013997:Time Factors
chemical_list: C508137:Creb1 protein, rat; D017362:Cyclic AMP Response Element-Binding Protein; D050828:Protein Inhibitors of Activated STAT; D020033:Protein Isoforms; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins
keywords: CREB; PIAS1; SUMOylation; phosphorylation; spatial learning and memory