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  • 1
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    SUMO1-dependent modulation of SERCA2a in heart failure (2011)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2011-09-09
    Description: The calcium-transporting ATPase ATP2A2, also known as SERCA2a, is a critical ATPase responsible for Ca(2+) re-uptake during excitation-contraction coupling. Impaired Ca(2+) uptake resulting from decreased expression and reduced activity of SERCA2a is a hallmark of heart failure. Accordingly, restoration of SERCA2a expression by gene transfer has proved to be effective in improving cardiac function in heart-failure patients, as well as in animal models. The small ubiquitin-related modifier (SUMO) can be conjugated to lysine residues of target proteins, and is involved in many cellular processes. Here we show that SERCA2a is SUMOylated at lysines 480 and 585 and that this SUMOylation is essential for preserving SERCA2a ATPase activity and stability in mouse and human cells. The levels of SUMO1 and the SUMOylation of SERCA2a itself were greatly reduced in failing hearts. SUMO1 restitution by adeno-associated-virus-mediated gene delivery maintained the protein abundance of SERCA2a and markedly improved cardiac function in mice with heart failure. This effect was comparable to SERCA2A gene delivery. Moreover, SUMO1 overexpression in isolated cardiomyocytes augmented contractility and accelerated Ca(2+) decay. Transgene-mediated SUMO1 overexpression rescued cardiac dysfunction induced by pressure overload concomitantly with increased SERCA2a function. By contrast, downregulation of SUMO1 using small hairpin RNA (shRNA) accelerated pressure-overload-induced deterioration of cardiac function and was accompanied by decreased SERCA2a function. However, knockdown of SERCA2a resulted in severe contractile dysfunction both in vitro and in vivo, which was not rescued by overexpression of SUMO1. Taken together, our data show that SUMOylation is a critical post-translational modification that regulates SERCA2a function, and provide a platform for the design of novel therapeutic strategies for heart failure.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3443490/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3443490/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kho, Changwon -- Lee, Ahyoung -- Jeong, Dongtak -- Oh, Jae Gyun -- Chaanine, Antoine H -- Kizana, Eddy -- Park, Woo Jin -- Hajjar, Roger J -- HL080498/HL/NHLBI NIH HHS/ -- HL093183/HL/NHLBI NIH HHS/ -- P20 HL100396/HL/NHLBI NIH HHS/ -- P20 HL100396-02/HL/NHLBI NIH HHS/ -- P20HL100396/HL/NHLBI NIH HHS/ -- R01 HL078731/HL/NHLBI NIH HHS/ -- R01 HL078731-04/HL/NHLBI NIH HHS/ -- R01 HL080498/HL/NHLBI NIH HHS/ -- R01 HL080498-05/HL/NHLBI NIH HHS/ -- R01 HL083156/HL/NHLBI NIH HHS/ -- R01 HL083156-05/HL/NHLBI NIH HHS/ -- R01 HL088434/HL/NHLBI NIH HHS/ -- R01 HL088434-02/HL/NHLBI NIH HHS/ -- England -- Nature. 2011 Sep 7;477(7366):601-5. doi: 10.1038/nature10407.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cardiovascular Research Center, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, Box 1030, New York, New York 10029, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21900893" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; HEK293 Cells ; Heart Failure/*metabolism/physiopathology ; Humans ; Lysine/metabolism ; Mice ; Rats ; Rats, Sprague-Dawley ; SUMO-1 Protein/genetics/*metabolism ; Sarcoplasmic Reticulum Calcium-Transporting ATPases/*metabolism ; *Sumoylation ; Sus scrofa
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    Probing cellular protein complexes using single-molecule pull-down (2011)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2011-05-27
    Description: Proteins perform most cellular functions in macromolecular complexes. The same protein often participates in different complexes to exhibit diverse functionality. Current ensemble approaches of identifying cellular protein interactions cannot reveal physiological permutations of these interactions. Here we describe a single-molecule pull-down (SiMPull) assay that combines the principles of a conventional pull-down assay with single-molecule fluorescence microscopy and enables direct visualization of individual cellular protein complexes. SiMPull can reveal how many proteins and of which kinds are present in the in vivo complex, as we show using protein kinase A. We then demonstrate a wide applicability to various signalling proteins found in the cytosol, membrane and cellular organelles, and to endogenous protein complexes from animal tissue extracts. The pulled-down proteins are functional and are used, without further processing, for single-molecule biochemical studies. SiMPull should provide a rapid, sensitive and robust platform for analysing protein assemblies in biological pathways.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3103084/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3103084/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jain, Ankur -- Liu, Ruijie -- Ramani, Biswarathan -- Arauz, Edwin -- Ishitsuka, Yuji -- Ragunathan, Kaushik -- Park, Jeehae -- Chen, Jie -- Xiang, Yang K -- Ha, Taekjip -- AI083025/AI/NIAID NIH HHS/ -- AR048914/AR/NIAMS NIH HHS/ -- GM065367/GM/NIGMS NIH HHS/ -- HL082846/HL/NHLBI NIH HHS/ -- R01 AR048914/AR/NIAMS NIH HHS/ -- R01 GM065367/GM/NIGMS NIH HHS/ -- R01 GM065367-09/GM/NIGMS NIH HHS/ -- R01 HL082846/HL/NHLBI NIH HHS/ -- U19 AI083025/AI/NIAID NIH HHS/ -- U19 AI083025-02/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 May 26;473(7348):484-8. doi: 10.1038/nature10016.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Biophysics and Computational Biology and Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21614075" target="_blank"〉PubMed〈/a〉
    Keywords: Bacterial Proteins/analysis/genetics/metabolism ; Cell Extracts/*chemistry ; Color ; Cyclic AMP-Dependent Protein Kinases/analysis/genetics/metabolism ; DNA Helicases/analysis/metabolism ; Fluorescence Resonance Energy Transfer ; Fluorescent Antibody Technique ; HEK293 Cells ; Humans ; Immunoprecipitation/*methods ; Luminescent Proteins/analysis/genetics/metabolism ; Microscopy, Fluorescence ; Mitochondrial Proteins/analysis/metabolism ; Multiprotein Complexes/*analysis/*chemistry/isolation & purification/metabolism ; Photobleaching ; Protein Binding ; Protein Interaction Mapping/*methods ; Receptors, Adrenergic, beta/analysis/metabolism ; Tissue Extracts/chemistry/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 3
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    Inhibition of miR-25 improves cardiac contractility in the failing heart (2014)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2014-03-29
    Description: Heart failure is characterized by a debilitating decline in cardiac function, and recent clinical trial results indicate that improving the contractility of heart muscle cells by boosting intracellular calcium handling might be an effective therapy. MicroRNAs (miRNAs) are dysregulated in heart failure but whether they control contractility or constitute therapeutic targets remains speculative. Using high-throughput functional screening of the human microRNAome, here we identify miRNAs that suppress intracellular calcium handling in heart muscle by interacting with messenger RNA encoding the sarcoplasmic reticulum calcium uptake pump SERCA2a (also known as ATP2A2). Of 875 miRNAs tested, miR-25 potently delayed calcium uptake kinetics in cardiomyocytes in vitro and was upregulated in heart failure, both in mice and humans. Whereas adeno-associated virus 9 (AAV9)-mediated overexpression of miR-25 in vivo resulted in a significant loss of contractile function, injection of an antisense oligonucleotide (antagomiR) against miR-25 markedly halted established heart failure in a mouse model, improving cardiac function and survival relative to a control antagomiR oligonucleotide. These data reveal that increased expression of endogenous miR-25 contributes to declining cardiac function during heart failure and suggest that it might be targeted therapeutically to restore function.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4131725/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4131725/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wahlquist, Christine -- Jeong, Dongtak -- Rojas-Munoz, Agustin -- Kho, Changwon -- Lee, Ahyoung -- Mitsuyama, Shinichi -- van Mil, Alain -- Park, Woo Jin -- Sluijter, Joost P G -- Doevendans, Pieter A F -- Hajjar, Roger J -- Mercola, Mark -- HHSN268201000045C/HL/NHLBI NIH HHS/ -- HHSN26820100045C/PHS HHS/ -- P01 HL098053/HL/NHLBI NIH HHS/ -- P01HL098053/HL/NHLBI NIH HHS/ -- P20 HL100396/HL/NHLBI NIH HHS/ -- P20HL100396/HL/NHLBI NIH HHS/ -- P30 AR061303/AR/NIAMS NIH HHS/ -- P30 CA030199/CA/NCI NIH HHS/ -- P30AR061303/AR/NIAMS NIH HHS/ -- P30CA030199/CA/NCI NIH HHS/ -- P50 HL112324/HL/NHLBI NIH HHS/ -- P50HL112324/HL/NHLBI NIH HHS/ -- R01 HL088434/HL/NHLBI NIH HHS/ -- R01 HL093183/HL/NHLBI NIH HHS/ -- R01 HL108176/HL/NHLBI NIH HHS/ -- R01 HL113601/HL/NHLBI NIH HHS/ -- R01HL088434/HL/NHLBI NIH HHS/ -- R01HL093183/HL/NHLBI NIH HHS/ -- R01HL108176/HL/NHLBI NIH HHS/ -- R01HL113601/HL/NHLBI NIH HHS/ -- S10 RR021084/RR/NCRR NIH HHS/ -- England -- Nature. 2014 Apr 24;508(7497):531-5. doi: 10.1038/nature13073. Epub 2014 Mar 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Bioengineering, University of California, San Diego, and the Muscle Development and Regeneration Program, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA [2]. ; 1] The Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA [2]. ; Department of Bioengineering, University of California, San Diego, and the Muscle Development and Regeneration Program, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA. ; The Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA. ; 1] Department of Bioengineering, University of California, San Diego, and the Muscle Development and Regeneration Program, Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA [2] Department of Cardiology, University Medical Center Utrecht and ICIN Netherlands Heart Institute, Heidelberglaan 100, room G02.523, 3584 CX Utrecht, The Netherlands. ; Global Research Laboratory, Gwangju Institute of Science and Technology, 123 Cheomdan-gwagiro, Buk-gu, Gwangju 500-712, South Korea. ; Department of Cardiology, University Medical Center Utrecht and ICIN Netherlands Heart Institute, Heidelberglaan 100, room G02.523, 3584 CX Utrecht, The Netherlands.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24670661" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Calcium/metabolism ; Dependovirus/genetics ; Disease Models, Animal ; HEK293 Cells ; Heart/drug effects/physiology/physiopathology ; Heart Failure/*genetics/*therapy ; Humans ; Kinetics ; Male ; Mice ; MicroRNAs/analysis/*antagonists & inhibitors/genetics/metabolism ; Myocardial Contraction/*drug effects ; Myocardium/metabolism ; Myocytes, Cardiac/metabolism ; Oligonucleotides, Antisense/genetics/metabolism/pharmacology ; RNA, Messenger/genetics/metabolism ; Sarcoplasmic Reticulum/metabolism ; Sarcoplasmic Reticulum Calcium-Transporting ATPases/genetics/metabolism ; Survival Analysis ; Up-Regulation/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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