Down-Regulation of c-Fos/c-Jun AP-1 Dimer Activity by Sumoylation

Bossis, Guillaume; Malnou, Cécile E.; Farràs, Rosa; Andermarcher, E.; Hipskind, Robert A.; Rodríguez, Manuel Sánchez; Schmidt, D; Müller, Stefan; Jariel-Encontre, Isabelle; Piechaczyk, Marc

doi:10.1128/mcb.25.16.6964-6979.2005

Cited by 175 publications

(169 citation statements)

References 68 publications

(110 reference statements)

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“…Conversely, a phosphomutant of c-jun with the N-terminal JNK phosphorylation sites deleted is more efficiently modified than the wild-type protein. A reciprocal regulation between the Erk kinase pathway and the SUMO system has also been observed on c-fos and Elk-1 (Bossis et al, 2003;Yang et al, 2003).…”

Section: Ap-1 Pathwaymentioning

confidence: 85%

“…While kinase pathways stimulate AP-1 function, SUMO modification attenuates its activity. Both c-jun and c-fos can undergo SUMO modification, and an AP-1 complex devoid of SUMOylation shows a strongly increased transactivation potential compared to wild-type AP-1 (Muller et al, 2000;Bossis et al, 2003). Interestingly, modification of SUMO sites in either c-jun or c-fos alone has only minor effects on transcriptional activity, implying a cooperative effect of SUMO modification in transcriptional repression of AP-1.…”

Section: Ap-1 Pathwaymentioning

confidence: 98%

“…Interestingly, modification of SUMO sites in either c-jun or c-fos alone has only minor effects on transcriptional activity, implying a cooperative effect of SUMO modification in transcriptional repression of AP-1. It is noteworthy that the SUMOylation of both c-jun and c-fos is stimulated by PIAS proteins (Kotaja et al, 2002b;Schmidt and Muller, 2002;Bossis et al, 2003).…”

Section: Ap-1 Pathwaymentioning

confidence: 99%

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SUMO: a regulator of gene expression and genome integrity

2004

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Post-translational modification with the ubiquitin-like SUMO protein is involved in the regulation of many cellular key processes. The SUMO system modulates signal transduction pathways, including cytokine, Wnt, growth factor and steroid hormone signalling. SUMO frequently restrains the activity of downstream transcription factors in these pathways presumably by facilitating the recruitment of corepressors or mediating the assembly of repressor complexes. Additionally, evidence is accumulating that SUMO controls pathways important for the surveillance of genome integrity. SUMO regulates the PML/p53 tumour suppressor network, a key determinant in the cellular response to DNA damage. Moreover, proteins that maintain genomic stability by functioning at the interface between DNA replication, recombination and repair processes undergo SUMOylation. We will discuss some key findings that exemplify the role of SUMO in transcriptional regulation and genome surveillance.

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Section: Ap-1 Pathwaymentioning

confidence: 85%

Section: Ap-1 Pathwaymentioning

confidence: 98%

Section: Ap-1 Pathwaymentioning

confidence: 99%

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SUMO: a regulator of gene expression and genome integrity

2004

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“…Taken together, these data suggest that phosphorylation of threonine 111 of K-bZIP has a negative effect on its repression activity and a positive effect on its transactivation function (data not shown). Thus, K-bZIP joins a growing list of transcriptional factors whose activities are modulated by sumoylation and phosphorylation in an antagonistic manner (8,56). Accordingly, we propose a model whereby vPK switches KbZIP from being a strong repressor of K-Rta, which targets immediate-early genes, to a transactivator that synergizes with K-Rta to activate early and late viral gene expression (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Kaposi's Sarcoma-Associated Herpesvirus-Encoded Protein Kinase and Its Interaction with K-bZIP

Izumiya

Geelen

et al. 2007

J Virol

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The oncogenic herpesvirus, Kaposi's sarcoma-associated herpesvirus, also identified as human herpesvirus 8, contains genes producing proteins that control transcription and influence cell signaling. Open reading frame 36 (ORF36) of this virus encodes a serine/threonine protein kinase, which is designated the viral protein kinase (vPK). Our recent efforts to elucidate the role of vPK in the viral life cycle have focused on identifying viral protein substrates and determining the effects of vPK-mediated phosphorylation on specific steps in viral replication. The vPK gene was transcribed into 4.2-kb and 3.6-kb mRNAs during the early and late phases of viral reactivation. vPK is colocalized with viral DNA replication/transcription compartments as marked by a polymerase processivity factor, and K-bZIP, a protein known to bind the viral DNA replication origin (Ori-Lyt) and to regulate viral transcription. The vPK physically associated with and strongly phosphorylated K-bZIP at threonine 111, a site also recognized by the cyclin-dependent kinase Cdk2. Both K-bZIP and vPK were corecruited to viral promoters targeted by K-bZIP as well as to the Ori-Lyt region. Phosphorylation of K-bZIP by vPK had a negative impact on K-bZIP transcription repression activity. The extent of posttranslational modification of K-bZIP by sumoylation, a process that influences its repression function, was decreased by vPK phosphorylation at threonine 111. Our data thus identify a new role of vPK as a modulator of viral transcription.Kaposi's sarcoma-associated herpesvirus (KSHV), also designated human herpesvirus 8, has been linked to several malignancies, including Kaposi's sarcoma, B-cell lymphomas, primary effusion lymphomas, and multicentric Castleman's disease in immunocompromised individuals (reviewed in reference 46). Kaposi's sarcoma is the most common malignancy associated with AIDS (45). The viral genome is doublestranded DNA, approximately 165 kbp, and encodes over 81 open reading frames (ORFs) (43). The majority of the ORFs are essential for viral replication and include genes necessary for viral DNA replication, transcription, and assembly of infectious particles (51). In addition, the KSHV genome contains a large number of ORFs with homology to known cellular genes. Several of these viral ORFs are implicated in modulating host immune responses, promoting angiogenesis, and dysregulating cell growth (14). A model for regulated expression of KSHV genes has been deduced from numerous genetic and biochemical studies of viral RNA patterns and activities of viral transactivators (22,31,39,49). As for other herpesviruses, KSHV genes in productive infection have been classified into the following temporally distinct classes: immediate-early, early, and late. This virus can also establish a latent state that is characterized by presence of a multicopy circular episome of viral DNA, which expresses a small subset of viral proteins. Productive (lytic) viral replication can be induced by treatment of latently infected cell lines with butyrate,...

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“…Although generally associated with repression, sumoylation can also result in enhanced transcriptional activation, as seen with the heat shock factors HSF1 and HSF2 (29). Adding further complexity, sumoylation of transcription factors may be reinforced or opposed by additional regulatory modifications, such as phosphorylation (30,31).…”

mentioning

confidence: 99%

Beads-on-a-String, Characterization of Ets-1 Sumoylated within Its Flexible N-terminal Sequence

Macauley

Errington

Schärpf

et al. 2006

Journal of Biological Chemistry

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Sumoylation regulates the activities of several members of the ETS transcription factor family. To provide a molecular framework for understanding this regulation, we have characterized the conjugation of Ets-1 with SUMO-1. Ets-1 is modified in vivo predominantly at a consensus sumoylation motif containing Lys-15. This lysine is located within the unstructured N-terminal segment of Ets-1 preceding its PNT domain. Using NMR spectroscopy, we demonstrate that the Ets-1 sumoylation motif associates with the substrate binding site on the SUMO-conjugating enzyme UBC9 (K d ϳ400 M) and that the PNT domain is not involved in this interaction. Ets-1 with Lys-15 mutated to an arginine still binds UBC9 with an affinity similar to the wild type protein, but is no longer sumoylated. NMR chemical shift and relaxation measurements reveal that the covalent attachment of mature SUMO-1, via its flexible C-terminal Gly-97, to Lys-15 of Ets-1 does not perturb the structure or dynamic properties of either protein. Therefore sumoylated Ets-1 behaves as "beads-on-a-string" with the two proteins tethered by flexible polypeptide segments containing the isopeptide linkage. Accordingly, SUMO-1 may mediate interactions of Ets-1 with signaling or transcriptional regulatory macromolecules by acting as a structurally independent docking module, rather than through the induction of a conformational change in either protein upon their covalent linkage. We also hypothesize that the flexibility of the linking polypeptide sequence may be a general feature contributing to the recognition of SUMO-modified proteins by their downstream effectors.The regulation of gene expression requires the spatial and temporal orchestration of a complex network of protein-protein and protein-DNA interactions. Central to the control of these interactions are a myriad of post-translational modifications. One such modification involves the reversible, covalent attachment of the ubiquitin-like protein SUMO.4 In addition to serving as an antagonist against ubiquitinmediated degradation, sumoylation affects a growing number of recognized biological processes, including nuclear transport, signal transduction, transcription, and DNA repair (recent reviews Refs. 1-5). However, despite extensive studies, the molecular mechanisms for this regulation, which likely arise through SUMO-dependent modulation of target protein interactions with other macromolecules, remain largely undefined (2, 6 -8).In contrast, the pathways for the sumoylation and desumoylation of target proteins are well established. After proteolytic maturation and ATP-dependent activation, SUMO family members are transferred from the heterodimeric E1-activating enzyme to Cys-93 in the single E2-conjugating enzyme, UBC9. Although E3-ligating enzymes, which facilitate the specificity and efficiency of sumoylation, have been identified, UBC9 is sufficient for conjugating SUMO to many proteins, at least in vitro (9). The final product is an isopeptide bond joining the C-terminal glycine carboxyl of SUMO with the side...

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Down-Regulation of c-Fos/c-Jun AP-1 Dimer Activity by Sumoylation

Abstract: Finally we report that the sumoylation of c-Fos is a dynamic process that can be reversed via multiple mechanisms. This supports the idea that this modification does not constitute a final inactivation step that necessarily precedes protein degradation.

Cited by 175 publications

References 68 publications

SUMO: a regulator of gene expression and genome integrity

SUMO: a regulator of gene expression and genome integrity

Kaposi's Sarcoma-Associated Herpesvirus-Encoded Protein Kinase and Its Interaction with K-bZIP

Beads-on-a-String, Characterization of Ets-1 Sumoylated within Its Flexible N-terminal Sequence

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