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Article ; Online: Viral DNA Binding Protein SUMOylation Promotes PML Nuclear Body Localization Next to Viral Replication Centers.

Stubbe, Miona / Mai, Julia / Paulus, Christina / Stubbe, Hans Christian / Berscheminski, Julia / Karimi, Maryam / Hofmann, Samuel / Weber, Elisabeth / Hadian, Kamyar / Hay, Ron / Groitl, Peter / Nevels, Michael / Dobner, Thomas / Schreiner, Sabrina

mBio

2020 Volume 11, Issue 2

Abstract: Human adenoviruses (HAdVs) have developed mechanisms to manipulate cellular antiviral measures to ensure proper DNA replication, with detailed processes far from being understood. Host cells repress incoming viral genomes through a network of ... ...

Abstract	Human adenoviruses (HAdVs) have developed mechanisms to manipulate cellular antiviral measures to ensure proper DNA replication, with detailed processes far from being understood. Host cells repress incoming viral genomes through a network of transcriptional regulators that normally control cellular homeostasis. The nuclear domains involved are promyelocytic leukemia protein nuclear bodies (PML-NBs), interferon-inducible, dot-like nuclear structures and hot spots of SUMO posttranslational modification (PTM). In HAdV-infected cells, such SUMO factories are found in close proximity to newly established viral replication centers (RCs) marked by the adenoviral DNA binding protein (DBP) E2A. Here, we show that E2A is a novel target of host SUMOylation, leading to PTMs supporting E2A function in promoting productive infection. Our data show that SUMOylated E2A interacts with PML. Decreasing SUMO-E2A protein levels by generating HAdV variants mutated in the three main SUMO conjugation motifs (SCMs) led to lower numbers of viral RCs and PML-NBs, and these two structures were no longer next to each other. Our data further indicate that SUMOylated E2A binds the host transcription factor Sp100A, promoting HAdV gene expression, and represents the molecular bridge between PML tracks and adjacent viral RCs. Consequently, E2A SCM mutations repressed late viral gene expression and progeny production. These data highlight a novel mechanism used by the virus to benefit from host antiviral responses by exploiting the cellular SUMO conjugation machinery.
MeSH term(s)	Adenovirus E2 Proteins/genetics ; Adenovirus E2 Proteins/metabolism ; Adenoviruses, Human/physiology ; Cell Line ; Host-Pathogen Interactions ; Humans ; Mutation ; Promyelocytic Leukemia Protein/genetics ; Promyelocytic Leukemia Protein/metabolism ; Protein Processing, Post-Translational ; Sumoylation ; Viral Proteins/genetics ; Viral Proteins/metabolism ; Virus Replication
Chemical Substances	Adenovirus E2 Proteins ; Promyelocytic Leukemia Protein ; Viral Proteins
Language	English
Publishing date	2020-03-17
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2557172-2
ISSN	2150-7511 ; 2161-2129
ISSN (online)	2150-7511
ISSN	2161-2129
DOI	10.1128/mBio.00049-20
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Article ; Online: The seven wonders of ubiquitin: a multi-interview: Personal insights into the ubiquitin field. Interview by Nonia Pariente.

Dikic, Ivan / Harper, Wade / Hay, Ron / Langer, Thomas / Rape, Michael / Sixma, Titia / Walczak, Henning

EMBO reports

2014 Volume 15, Issue 1, Page(s) 7–11

MeSH term(s)	Humans ; Proteasome Endopeptidase Complex/physiology ; Ubiquitin/physiology ; Ubiquitination
Chemical Substances	Ubiquitin ; Proteasome Endopeptidase Complex (EC 3.4.25.1)
Language	English
Publishing date	2014-01-08
Publishing country	England
Document type	Interview ; Portrait
ZDB-ID	2020896-0
ISSN	1469-3178 ; 1469-221X
ISSN (online)	1469-3178
ISSN	1469-221X
DOI	10.1002/embr.201338230
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Zs.A 5433: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: E1B-55K-Mediated Regulation of RNF4 SUMO-Targeted Ubiquitin Ligase Promotes Human Adenovirus Gene Expression.

Müncheberg, Sarah / Hay, Ron T / Ip, Wing H / Meyer, Tina / Weiß, Christina / Brenke, Jara / Masser, Sawinee / Hadian, Kamyar / Dobner, Thomas / Schreiner, Sabrina

Journal of virology

2018 Volume 92, Issue 13

Abstract: Human adenovirus (HAdV) E1B-55K is a multifunctional regulator of productive viral replication and oncogenic transformation in nonpermissive mammalian cells. These functions depend on E1B-55K's posttranslational modification with the SUMO protein and its ...

Abstract	Human adenovirus (HAdV) E1B-55K is a multifunctional regulator of productive viral replication and oncogenic transformation in nonpermissive mammalian cells. These functions depend on E1B-55K's posttranslational modification with the SUMO protein and its binding to HAdV E4orf6. Both early viral proteins recruit specific host factors to form an E3 ubiquitin ligase complex that targets antiviral host substrates for proteasomal degradation. Recently, we reported that the PML-NB-associated factor Daxx represses efficient HAdV productive infection and is proteasomally degraded via a SUMO-E1B-55K-dependent, E4orf6-independent pathway, the details of which remained to be established. RNF4, a cellular SUMO-targeted ubiquitin ligase (STUbL), induces ubiquitinylation of specific SUMOylated proteins and plays an essential role during DNA repair. Here, we show that E1B-55K recruits RNF4 to the insoluble nuclear matrix fraction of the infected cell to support RNF4/Daxx association, promoting Daxx PTM and thus inhibiting this antiviral factor. Removing RNF4 from infected cells using RNA interference resulted in blocking the proper establishment of viral replication centers and significantly diminished viral gene expression. These results provide a model for how HAdV antagonize the antiviral host responses by exploiting the functional capacity of cellular STUbLs. Thus, RNF4 and its STUbL function represent a positive factor during lytic infection and a novel candidate for future therapeutic antiviral intervention strategies.
MeSH term(s)	Adaptor Proteins, Signal Transducing/genetics ; Adaptor Proteins, Signal Transducing/metabolism ; Adenovirus E1B Proteins/genetics ; Adenovirus E1B Proteins/metabolism ; Adenovirus Infections, Human/metabolism ; Adenovirus Infections, Human/virology ; Adenoviruses, Human/physiology ; HEK293 Cells ; Host-Pathogen Interactions ; Humans ; Intranuclear Inclusion Bodies ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Protein Processing, Post-Translational ; SUMO-1 Protein/genetics ; SUMO-1 Protein/metabolism ; Sumoylation ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Ubiquitin/metabolism ; Ubiquitin-Protein Ligases/genetics ; Ubiquitin-Protein Ligases/metabolism ; Virus Replication
Chemical Substances	Adaptor Proteins, Signal Transducing ; Adenovirus E1B Proteins ; DAXX protein, human ; Nuclear Proteins ; RNF4 protein, human ; SUMO-1 Protein ; Transcription Factors ; Ubiquitin ; Ubiquitin-Protein Ligases (EC 2.3.2.27)
Language	English
Publishing date	2018-06-13
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.00164-18
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Article ; Online: HSP90 protein stabilizes unloaded argonaute complexes and microscopic P-bodies in human cells.

Johnston, Michael / Geoffroy, Marie-Claude / Sobala, Andrew / Hay, Ron / Hutvagner, Gyorgy

Molecular biology of the cell

2010 Volume 21, Issue 9, Page(s) 1462–1469

Abstract: Key components of the miRNA-mediated gene regulation pathway are localized in cytoplasmic processing bodies (P-bodies). Mounting evidence suggests that the presence of microscopic P-bodies are not always required for miRNA-mediated gene regulation. Here ... ...

Abstract	Key components of the miRNA-mediated gene regulation pathway are localized in cytoplasmic processing bodies (P-bodies). Mounting evidence suggests that the presence of microscopic P-bodies are not always required for miRNA-mediated gene regulation. Here we have shown that geldanamycin, a well-characterized HSP90 inhibitor, abolishes P-bodies and significantly reduces Argonaute and GW182 protein levels but does not affect the miRNA level and the efficiency of miRNA-mediated gene repression; however, it significantly impairs siRNA loading and the efficacy of exogenous siRNA. Our data suggests that HSP90 protein chaperones Argonautes before binding RNA and may facilitate efficient loading of small RNA.
MeSH term(s)	Argonaute Proteins ; Autoantigens/genetics ; Autoantigens/metabolism ; Benzoquinones/pharmacology ; Blotting, Northern ; Blotting, Western ; Cell Line ; Cell Line, Tumor ; Cytoplasmic Granules/drug effects ; Cytoplasmic Granules/metabolism ; Eukaryotic Initiation Factor-2/genetics ; Eukaryotic Initiation Factor-2/metabolism ; Gene Expression ; HSP90 Heat-Shock Proteins/antagonists & inhibitors ; HSP90 Heat-Shock Proteins/genetics ; HSP90 Heat-Shock Proteins/metabolism ; HeLa Cells ; Humans ; Lactams, Macrocyclic/pharmacology ; Luciferases/genetics ; Luciferases/metabolism ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Microscopy, Fluorescence ; Protein Binding ; RNA Interference ; RNA-Binding Proteins ; Signal Transduction/drug effects ; Transfection
Chemical Substances	AGO2 protein, human ; Argonaute Proteins ; Autoantigens ; Benzoquinones ; Eukaryotic Initiation Factor-2 ; HSP90 Heat-Shock Proteins ; Lactams, Macrocyclic ; MicroRNAs ; RNA-Binding Proteins ; TNRC6A protein, human ; Luciferases (EC 1.13.12.-) ; geldanamycin (Z3K3VJ16KU)
Language	English
Publishing date	2010-03-17
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1098979-1
ISSN	1939-4586 ; 1059-1524
ISSN (online)	1939-4586
ISSN	1059-1524
DOI	10.1091/mbc.E09-10-0885
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Zs.A 2853: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 410: Show issues

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Article ; Online: Heterologous SUMO-2/3-ubiquitin chains optimize IκBα degradation and NF-κB activity.

Aillet, Fabienne / Lopitz-Otsoa, Fernando / Egaña, Isabel / Hjerpe, Roland / Fraser, Paul / Hay, Ron T / Rodriguez, Manuel S / Lang, Valérie

PloS one

2012 Volume 7, Issue 12, Page(s) e51672

Abstract: The NF-κB pathway is regulated by SUMOylation at least at three levels: the inhibitory molecule IκBα, the IKK subunit γ/NEMO and the p52 precursor p100. Here we investigate the role of SUMO-2/3 in the degradation of IκBα and activation of NF-κB mediated ... ...

Abstract	The NF-κB pathway is regulated by SUMOylation at least at three levels: the inhibitory molecule IκBα, the IKK subunit γ/NEMO and the p52 precursor p100. Here we investigate the role of SUMO-2/3 in the degradation of IκBα and activation of NF-κB mediated by TNFα. We found that under conditions of deficient SUMOylation, an important delay in both TNFα-mediated proteolysis of IκBα and NF-κB dependent transcription occurs. In vitro and ex vivo approaches, including the use of ubiquitin-traps (TUBEs), revealed the formation of chains on IκBα containing SUMO-2/3 and ubiquitin after TNFα stimulation. The integration of SUMO-2/3 appears to promote the formation of ubiquitin chains on IκBα after activation of the TNFα signalling pathway. Furthermore, heterologous chains of SUMO-2/3 and ubiquitin promote a more efficient degradation of IκBα by the 26S proteasome in vitro compared to chains of either SUMO-2/3 or ubiquitin alone. Consistently, Ubc9 silencing reduced the capture of IκBα modified with SUMO-ubiquitin hybrid chains that display a defective proteasome-mediated degradation. Thus, hybrid SUMO-2/3-ubiquitin chains increase the susceptibility of modified IκBα to the action of 26S proteasome, contributing to the optimal control of NF-κB activity after TNFα-stimulation.
MeSH term(s)	Cytoplasm/metabolism ; HeLa Cells ; Humans ; I-kappa B Proteins/metabolism ; NF-KappaB Inhibitor alpha ; NF-kappa B/metabolism ; Phosphorylation/drug effects ; Proteasome Endopeptidase Complex/metabolism ; Proteolysis ; Signal Transduction/drug effects ; Small Ubiquitin-Related Modifier Proteins/metabolism ; Sumoylation ; Tumor Necrosis Factor-alpha/pharmacology ; Ubiquitin/metabolism ; Ubiquitin-Conjugating Enzymes/metabolism ; Ubiquitins/metabolism
Chemical Substances	I-kappa B Proteins ; NF-kappa B ; NFKBIA protein, human ; SUMO2 protein, human ; SUMO3 protein, human ; Small Ubiquitin-Related Modifier Proteins ; Tumor Necrosis Factor-alpha ; Ubiquitin ; Ubiquitins ; NF-KappaB Inhibitor alpha (139874-52-5) ; Ubiquitin-Conjugating Enzymes (EC 2.3.2.23) ; Proteasome Endopeptidase Complex (EC 3.4.25.1) ; ubiquitin-conjugating enzyme UBC9 (EC 6.3.2.-)
Language	English
Publishing date	2012-12-20
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0051672
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Article ; Online: Nuclear factor-kappaB activation via tyrosine phosphorylation of inhibitor kappaB-alpha is crucial for ciliary neurotrophic factor-promoted neurite growth from developing neurons.

Gallagher, Denis / Gutierrez, Humberto / Gavalda, Nuria / O'Keeffe, Gerard / Hay, Ron / Davies, Alun M

The Journal of neuroscience : the official journal of the Society for Neuroscience

2007 Volume 27, Issue 36, Page(s) 9664–9669

Abstract: The cytokine ciliary neurotrophic factor (CNTF) promotes the growth of neural processes from many kinds of neurons in the developing and regenerating adult nervous system, but the intracellular signaling mechanisms mediating this important function of ... ...

Abstract	The cytokine ciliary neurotrophic factor (CNTF) promotes the growth of neural processes from many kinds of neurons in the developing and regenerating adult nervous system, but the intracellular signaling mechanisms mediating this important function of CNTF are poorly understood. Here, we show that CNTF activates the nuclear factor-kappaB (NF-kappaB) transcriptional system in neonatal sensory neurons and that blocking NF-kappaB-dependent transcription inhibits CNTF-promoted neurite growth. Selectively blocking NF-kappaB activation by the noncanonical pathway that requires tyrosine phosphorylation of inhibitor kappaB-alpha (IkappaB-alpha), but not by the canonical pathway that requires serine phosphorylation of IkappaB-alpha, also effectively inhibits CNTF-promoted neurite growth. CNTF treatment activates spleen tyrosine kinase (SYK) whose substrates include IkappaB-alpha. CNTF-induced SYK phosphorylation is rapidly followed by increased tyrosine phosphorylation of IkappaB-alpha, and blocking SYK activation or tyrosine phosphorylation of IkappaB-alpha prevents CNTF-induced NF-kappaB activation and CNTF-promoted neurite growth. These findings demonstrate that NF-kappaB signaling by an unusual activation mechanism is essential for the ability of CNTF to promote the growth of neural processes in the developing nervous system.
MeSH term(s)	Animals ; Animals, Newborn ; Cells, Cultured ; Ciliary Neurotrophic Factor/pharmacology ; Ciliary Neurotrophic Factor/physiology ; Enzyme Activation/drug effects ; I-kappa B Proteins/metabolism ; Intracellular Signaling Peptides and Proteins/metabolism ; Mice ; NF-KappaB Inhibitor alpha ; NF-kappa B/metabolism ; Neurites/drug effects ; Neurites/physiology ; Neurons, Afferent/drug effects ; Neurons, Afferent/physiology ; Neurons, Afferent/ultrastructure ; Nodose Ganglion/cytology ; Oligonucleotides/pharmacology ; Phosphorylation/drug effects ; Protein-Tyrosine Kinases/metabolism ; Signal Transduction/drug effects ; Signal Transduction/physiology ; Syk Kinase ; Transcription, Genetic/drug effects ; Tyrosine/metabolism
Chemical Substances	Ciliary Neurotrophic Factor ; I-kappa B Proteins ; Intracellular Signaling Peptides and Proteins ; NF-kappa B ; Nfkbia protein, mouse ; Oligonucleotides ; NF-KappaB Inhibitor alpha (139874-52-5) ; Tyrosine (42HK56048U) ; Protein-Tyrosine Kinases (EC 2.7.10.1) ; Syk Kinase (EC 2.7.10.2) ; Syk protein, mouse (EC 2.7.10.2)
Language	English
Publishing date	2007-08-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	604637-x
ISSN	1529-2401 ; 0270-6474
ISSN (online)	1529-2401
ISSN	0270-6474
DOI	10.1523/JNEUROSCI.0608-07.2007
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Article: Dynamic interplay of the SUMO and ERK pathways in regulating Elk-1 transcriptional activity.

Yang, Shen-Hsi / Jaffray, Ellis / Hay, Ron T / Sharrocks, Andrew D

Molecular cell

2003 Volume 12, Issue 1, Page(s) 63–74

Abstract: The ETS domain transcription factor Elk-1 is a direct target of the MAP kinase pathways. Phosphorylation of the Elk-1 transcriptional activation domain by MAP kinases triggers its activation. However, Elk-1 also contains two domains with repressive ... ...

Abstract	The ETS domain transcription factor Elk-1 is a direct target of the MAP kinase pathways. Phosphorylation of the Elk-1 transcriptional activation domain by MAP kinases triggers its activation. However, Elk-1 also contains two domains with repressive activities. One of these, the R motif, appears to function by suppressing the activity of the activation domain. Here, we demonstrate that SUMO modification of the R motif is required for this repressive activity. A dynamic interplay exists between the activating ERK MAP kinase pathway and the repressive SUMO pathway. ERK pathway activation leads to both phosphorylation of Elk-1 and loss of SUMO conjugation and, hence, to the loss of the repressive activity of the R motif. Thus, the reciprocal regulation of the activation and repressive activities are coupled by MAP kinase modification of Elk-1.
MeSH term(s)	Animals ; Cell Line ; DNA-Binding Proteins ; Eukaryotic Cells/enzymology ; Genes, Regulator/genetics ; Humans ; Mitogen-Activated Protein Kinases/genetics ; Mitogen-Activated Protein Kinases/metabolism ; Protein Structure, Tertiary/genetics ; Proto-Oncogene Proteins/genetics ; Proto-Oncogene Proteins/metabolism ; Repressor Proteins/genetics ; Repressor Proteins/metabolism ; SUMO-1 Protein/genetics ; SUMO-1 Protein/metabolism ; Transcription Factors ; Transcription, Genetic/genetics ; ets-Domain Protein Elk-1
Chemical Substances	DNA-Binding Proteins ; ELK1 protein, human ; Proto-Oncogene Proteins ; Repressor Proteins ; SUMO-1 Protein ; Transcription Factors ; ets-Domain Protein Elk-1 ; Mitogen-Activated Protein Kinases (EC 2.7.11.24)
Language	English
Publishing date	2003-07-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/s1097-2765(03)00265-x
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Zs.A 5055: Show issues

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Article ; Online: Sp100 isoform-specific regulation of human adenovirus 5 gene expression.

Berscheminski, Julia / Wimmer, Peter / Brun, Juliane / Ip, Wing Hang / Groitl, Peter / Horlacher, Tim / Jaffray, Ellis / Hay, Ron T / Dobner, Thomas / Schreiner, Sabrina

Journal of virology

2014 Volume 88, Issue 11, Page(s) 6076–6092

Abstract: Unlabelled: Promyelocytic leukemia nuclear bodies (PML-NBs) are nuclear structures that accumulate intrinsic host factors to restrict viral infections. To ensure viral replication, these must be limited by expression of viral early regulatory proteins ... ...

Abstract	Unlabelled: Promyelocytic leukemia nuclear bodies (PML-NBs) are nuclear structures that accumulate intrinsic host factors to restrict viral infections. To ensure viral replication, these must be limited by expression of viral early regulatory proteins that functionally inhibit PML-NB-associated antiviral effects. To benefit from the activating capabilities of Sp100A and simultaneously limit repression by Sp100B, -C, and -HMG, adenoviruses (Ads) employ several features to selectively and individually target these isoforms. Ads induce relocalization of Sp100B, -C, and -HMG from PML-NBs prior to association with viral replication centers. In contrast, Sp100A is kept at the PML tracks that surround the newly formed viral replication centers as designated sites of active transcription. We concluded that the host restriction factors Sp100B, -C, and -HMG are potentially inactivated by active displacement from these sites, whereas Sp100A is retained to amplify Ad gene expression. Ad-dependent loss of Sp100 SUMOylation is another crucial part of the virus repertoire to counteract intrinsic immunity by circumventing Sp100 association with HP1, therefore limiting chromatin condensation. We provide evidence that Ad selectively counteracts antiviral responses and, at the same time, benefits from PML-NB-associated components which support viral gene expression by actively recruiting them to PML track-like structures. Our findings provide insights into novel strategies for manipulating transcriptional regulation to either inactivate or amplify viral gene expression. Importance: We describe an adenoviral evasion strategy that involves isoform-specific and active manipulation of the PML-associated restriction factor Sp100. Recently, we reported that the adenoviral transactivator E1A targets PML-II to efficiently activate viral transcription. In contrast, the PML-associated proteins Daxx and ATRX are inhibited by early viral factors. We show that this concept is more intricate and significant than originally believed, since adenoviruses apparently take advantage of specific PML-NB-associated proteins and simultaneously inhibit antiviral measures to maintain the viral infectious program. Specifically, we observed Ad-induced relocalization of the Sp100 isoforms B, C, and HMG from PML-NBs juxtaposed with viral replication centers. In contrast, Sp100A is retained at Ad-induced PML tracks that surround the newly formed viral replication centers, acting as designated sites of active transcription. The host restriction factors Sp100B, -C, and -HMG are potentially inactivated by active displacement from these sites, whereas Sp100A is retained to amplify Ad gene expression.
MeSH term(s)	Adenovirus Infections, Human/immunology ; Adenoviruses, Human/genetics ; Adenoviruses, Human/metabolism ; Antigens, Nuclear/metabolism ; Autoantigens/metabolism ; Cell Line ; DNA Primers/genetics ; Fluorescent Antibody Technique, Indirect ; Gene Expression Regulation, Viral/genetics ; Humans ; Immunity, Innate/immunology ; Immunoblotting ; In Situ Hybridization ; Luciferases ; Nuclear Proteins/metabolism ; Promyelocytic Leukemia Protein ; Protein Isoforms/metabolism ; Real-Time Polymerase Chain Reaction ; Sumoylation ; Transcription Factors/metabolism ; Tumor Suppressor Proteins/metabolism
Chemical Substances	Antigens, Nuclear ; Autoantigens ; DNA Primers ; Nuclear Proteins ; Promyelocytic Leukemia Protein ; Protein Isoforms ; Transcription Factors ; Tumor Suppressor Proteins ; SP100 protein, human (135844-47-2) ; PML protein, human (143220-95-5) ; Luciferases (EC 1.13.12.-)
Language	English
Publishing date	2014-03-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.00469-14
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Zs.A 609: Show issues

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Article: SUMO and transcriptional repression: dynamic interactions between the MAP kinase and SUMO pathways.

Yang, Shen-Hsi / Jaffray, Ellis / Senthinathan, Biruntha / Hay, Ron T / Sharrocks, Andrew D

Cell cycle (Georgetown, Tex.)

2003 Volume 2, Issue 6, Page(s) 528–530

Abstract: SUMO modification of proteins is being increasingly linked with transcriptional repression. We recently demonstrated that SUMO modification also downregulates the transcriptional activity of the ETS-domain transcription factor Elk-1. However, as Elk-1 ... ...

Abstract	SUMO modification of proteins is being increasingly linked with transcriptional repression. We recently demonstrated that SUMO modification also downregulates the transcriptional activity of the ETS-domain transcription factor Elk-1. However, as Elk-1 becomes activated through MAP kinase-mediated phosphorylation, the SUMO modification is lost, providing an elegant molecular switch that promotes the loss of repressive activities at the same time as permitting the recruitment of coactivator proteins. However, the mechanism by which SUMO promotes transcriptional repression remains enigmatic.
MeSH term(s)	Animals ; DNA-Binding Proteins ; Gene Expression Regulation ; Humans ; Mitogen-Activated Protein Kinases/metabolism ; Proto-Oncogene Proteins/metabolism ; SUMO-1 Protein/metabolism ; Transcription Factors ; Transcription, Genetic ; ets-Domain Protein Elk-1
Chemical Substances	DNA-Binding Proteins ; ELK1 protein, human ; Proto-Oncogene Proteins ; SUMO-1 Protein ; Transcription Factors ; ets-Domain Protein Elk-1 ; Mitogen-Activated Protein Kinases (EC 2.7.11.24)
Language	English
Publishing date	2003-09-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2146183-1
ISSN	1551-4005 ; 1538-4101 ; 1554-8627
ISSN (online)	1551-4005
ISSN	1538-4101 ; 1554-8627
DOI	10.4161/cc.2.6.597
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Zs.A 5881: Show issues

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Article ; Online: Selective SUMO modification of cAMP-specific phosphodiesterase-4D5 (PDE4D5) regulates the functional consequences of phosphorylation by PKA and ERK.

Li, Xiang / Vadrevu, Suryakiran / Dunlop, Allan / Day, Jon / Advant, Noopur / Troeger, Jessica / Klussmann, Enno / Jaffrey, Ellis / Hay, Ron T / Adams, David R / Houslay, Miles D / Baillie, George S

The Biochemical journal

2010 Volume 428, Issue 1, Page(s) 55–65

Abstract: Enzymes from the PDE (phosphodiesterase) 4 cAMP-specific PDE family are crucial for the maintenance of compartmentalized cAMP responses in many cell types. Regulation of PDE activity can be achieved via post-translational modification such as ... ...

Abstract	Enzymes from the PDE (phosphodiesterase) 4 cAMP-specific PDE family are crucial for the maintenance of compartmentalized cAMP responses in many cell types. Regulation of PDE activity can be achieved via post-translational modification such as phosphorylation by ERK (extracellular-signal-regulated kinase) MAPKs (mitogen-activated protein kinases) and PKA (protein kinase A). In the present paper, we report for the first time that PDE4 isoforms from the PDE4A and PDE4D subfamilies can be selectively modified by SUMO (small ubiquitin-related modifier). We have identified a single SUMO site within a consensus tetrapeptide motif, PsiKXE (where Psi represents a hydrophobic residue), which lies in the catalytic unit of these enzymes. SUMO modification of PDE4 at this site was observed upon overexpression of the SUMO E3 ligase PIASy [protein inhibitor of activated STAT (signal transducer and activator of transcription) Y] in HEK (human embryonic kidney)-293 cells and we identify PIASy as a novel binding partner for long PDE4 isoforms. Site-directed mutagenesis of the acceptor lysine residue ablated conjugation of PDE4 with SUMO, suggesting the presence of a single SUMO site in the first subdomain of the conserved PDE4 catalytic unit. This observation was supported by both cell-free in vitro SUMOylation assays and analysis of SUMOylated spot-immobilized peptide arrays. SUMO modification of long PDE4 isoforms serves to augment their activation by PKA phosphorylation and repress their inhibition by ERK phosphorylation. Following ligation of beta-adrenergic receptors, SUMOylation of PDE4 isoforms sufficiently amplified PKA-stimulated PDE4 activity to reduce markedly the PKA phosphorylation status of the beta2-adrenergic receptor. These results highlight a new means whereby cells might achieve the selective regulation of the activity of cAMP-specific PDE4 enyzmes.
MeSH term(s)	Amino Acid Sequence ; Animals ; COS Cells ; Cells, Cultured ; Cercopithecus aethiops ; Cyclic AMP-Dependent Protein Kinases/metabolism ; Cyclic Nucleotide Phosphodiesterases, Type 4/genetics ; Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Humans ; Molecular Sequence Data ; Phosphorylation ; Protein Conformation ; Protein Isoforms/genetics ; Protein Isoforms/metabolism ; SUMO-1 Protein/metabolism ; Signal Transduction
Chemical Substances	Protein Isoforms ; SUMO-1 Protein ; Cyclic AMP-Dependent Protein Kinases (EC 2.7.11.11) ; Extracellular Signal-Regulated MAP Kinases (EC 2.7.11.24) ; Cyclic Nucleotide Phosphodiesterases, Type 4 (EC 3.1.4.17)
Language	English
Publishing date	2010-04-28
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2969-5
ISSN	1470-8728 ; 0006-2936 ; 0306-3275 ; 0264-6021
ISSN (online)	1470-8728
ISSN	0006-2936 ; 0306-3275 ; 0264-6021
DOI	10.1042/BJ20091672
Database	MEDical Literature Analysis and Retrieval System OnLINE

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