Viruses and sumoylation: recent highlights

Boggio, Roberto; Chiocca, Susanna

doi:10.1016/j.mib.2006.06.008

Cited by 86 publications

(94 citation statements)

References 54 publications

(59 reference statements)

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“…Viruses can counteract or enhance the host's sumoylation to evade the immune response and antagonize apoptosis, while some viruses exploit the host's sumoylation machinery to sumoylate the viral components which are necessary to perform viral functions (48). It has been reported that KSHV modulates the SUMO pathway through RTA/ORF50, K-bZIP/K8, and vPK/ORF36 during lytic replication as well as LANA/ORF73 and viral IRF3 (IRF3)/K10.5/LANA-2 during latency (27,35,(49)(50)(51)(52)(53)(54)(55)(56).…”

Section: Discussionmentioning

confidence: 99%

The Latency-Associated Nuclear Antigen of Kaposi's Sarcoma-Associated Herpesvirus Inhibits Expression of SUMO/Sentrin-Specific Peptidase 6 To Facilitate Establishment of Latency

Lin

Sun

Zhang

et al. 2017

J Virol

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Kaposi's sarcoma-associated herpesvirus (KSHV), which belongs to the Gammaherpesviridae, typically displays two different phases in its life cycle, the latent phase and the lytic phase. Latency-associated nuclear antigen (LANA), the primary viral product during latency, has been reported to bind to a series of cellular gene promoters to modulate gene transcription. To systemically elucidate the cellular genes regulated by LANA, we identified genome-wide LANA binding sites by chromatin immunoprecipitation coupled with sequencing (ChIP-seq). We stratified ChIP-seq data and found that LANA might be involved in the macromolecule catabolic process. Specifically, we found and verified that LANA could directly bind to the promoter of the SUMO/sentrin-specific peptidase 6 (SENP6) gene in vivo and in vitro. LANA could repress SENP6 promoter activity in a dose-dependent manner in a reporter gene assay. LANA expression was sufficient to inhibit endogenous SENP6 expression at both the RNA and protein levels. Moreover, SENP6 overexpression in KSHV-infected cells reduced LANA at the protein level. Mechanistically, we found that SENP6 could interact with LANA and reduce the formation of sumoylated LANA, which relies on the desumoylation ability of SENP6. During de novo infection, SENP6 overexpression would decrease the abundance of LANA and enhance viral gene expression, which would hamper the establishment of latency. Taken together, these data suggest that KSHV-encoded LANA could inhibit SENP6 expression to regulate the abundance of itself, which may play an important role in controlling the establishment of latency.IMPORTANCE LANA, as a key latent protein produced by KSHV, is responsible for episome persistence and regulates viral reactivation. In the present study, our results demonstrated that LANA could bind to the promoter region of the SENP6 gene and inhibit SENP6 expression while the regulated SENP6 could in turn modulate the abundance of LANA through desumoylation. This delicate regulation may provide important insights to explain the abundance of LANA during KSHV latency.

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Section: Discussionmentioning

confidence: 99%

The Latency-Associated Nuclear Antigen of Kaposi's Sarcoma-Associated Herpesvirus Inhibits Expression of SUMO/Sentrin-Specific Peptidase 6 To Facilitate Establishment of Latency

Lin

Sun

Zhang

et al. 2017

J Virol

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“…Viral proteins were among the first substrates found to be posttranslationally modified by the small ubiquitin-like modifier (SUMO) protein, and SUMOylation seems to facilitate viral infections of the host cells (8). SUMO is a member of the larger family of ubiquitinlike proteins, which shares about 18% sequence identity to ubiquitin and is structurally quite similar (31).…”

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confidence: 99%

Regulation of Vaccinia Virus E3 Protein by Small Ubiquitin-Like Modifier Proteins

González-Santamaría

Campagna

García

et al. 2011

J Virol

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The vaccinia virus (VACV) E3 protein is essential for virulence and has antiapoptotic activity and the ability to impair the host innate immune response. Here we demonstrate that E3 interacts with SUMO1 through a small ubiquitin-like modifier (SUMO)-interacting motif (SIM). SIM integrity is required for maintaining the stability of the viral protein and for the covalent conjugation of E3 to SUMO1 or SUMO2, a modification that has a negative effect on the E3 transcriptional transactivation of the p53-upregulated modulator of apoptosis (PUMA) and APAF-1 genes. We also demonstrate that E3 is ubiquitinated, a modification that does not destabilize the wild-type protein but triggers the degradation of an E3-⌬SIM mutant. This report constitutes the first demonstration of the important roles that both SUMO and ubiquitin play in the regulation of the VACV protein E3.

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“…Since the discovery of SUMO1 in 1996, the list of proteins that have been reported to be modified by SUMO1 has grown. Viral proteins were among the first substrates found to be post-translationally modified by SUMO, and sumoylation seems to facilitate viral infection of host cells (Boggio & Chiocca, 2006 To determine whether LANA2 could be modified by SUMO conjugation, in vitro sumoylation assays using 35 Smethionine-labelled in vitro-translated LANA2 protein were performed as described previously by Campagna et al (2010). Incubation of the in vitro sumoylation reaction with SUMO1 revealed a broad additional band approximately 20 kDa larger than the LANA2 band corresponding to LANA2-SUMO1 protein (Fig.…”

mentioning

confidence: 99%

mentioning

confidence: 99%

Covalent modification by SUMO is required for efficient disruption of PML oncogenic domains by Kaposi's sarcoma-associated herpesvirus latent protein LANA2

Marcos-Villar

Campagna

Lopitz‐Otsoa

et al. 2010

Journal of General Virology

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The multifunctional Kaposi's sarcoma-associated herpesvirus (KSHV) latent protein latencyassociated nuclear antigen 2 (LANA2) has a critical role in KSHV-induced B-cell malignancies. LANA2 increases the level of small ubiquitin-like modifier (SUMO)2-ubiquitin-modified PML and induces the disruption of PML oncogenic domains (PODs) by a process that requires a noncovalent SUMO interaction domain (SIM) in LANA2. We now demonstrate that LANA2 is covalently conjugated to SUMO1 and SUMO2 both in vitro and in latently KSHV-infected B-cells. We show that a LANA2 SIM mutant exhibits a slightly altered sumoylation pattern, which suggests that non-covalent SUMO interactions represent a mechanism for determining SUMO substrate recognition and modification. In addition, several lysine residues were mapped as SUMO conjugation sites. A sumoylation-deficient mutant shows impaired ability to induce disruption of PODs, which suggests that either directly bound or covalently conjugated SUMO moieties may act as a bridge for interaction between LANA2 and other SUMO-modified or SUMO-interacting proteins required for disruption of PODs.Latency-associated nuclear antigen 2 (LANA2; also known as viral interferon regulatory factor 3) is a Kaposi's sarcoma-associated herpesvirus (KSHV) latent protein encoded by ORFK10.5 and is detected exclusively in Bcells infected with the virus (Lubyova & Pitha, 2000;Rivas et al., 2001). LANA2 has been suggested to play an important role in KSHV-mediated tumorigenesis, because of its ability to inhibit p53 function (Rivas et al., 2001), dsRNA-activated protein kinase R (PKR)-dependent apoptosis (Esteban et al., 2003), nuclear factor kB activity (Seo et al., 2004), interferon regulatory factor 7-mediated interferon signal transduction (Joo et al., 2007) and virusmediated transcriptional activation of the a-interferon promoter (Lubyova & Pitha, 2000). LANA2 also stabilizes and induces the transcriptional activity of hypoxia-inducible factor-1a (Shin et al., 2008) and disrupts PML oncogenic domains (PODs) (Marcos-Villar et al., 2009). Moreover, LANA2 has been shown to be required for the survival of cells infected with KSHV alone or dually infected by Epstein-Barr virus and KSHV (Wies et al., 2008). The multifunctional nature of LANA2 suggests that post-translational modifications may modulate its activities.Small ubiquitin-like modifier (SUMO) is an 11.5 kDa protein that is conjugated to multiple proteins and has been reported to exhibit multiple effects, including modulation of protein stability, subcellular localization and activity (Zhao, 2007). Since the discovery of SUMO1 in 1996, the list of proteins that have been reported to be modified by SUMO1 has grown. Viral proteins were among the first substrates found to be post-translationally modified by SUMO, and sumoylation seems to facilitate viral infection of host cells (Boggio & Chiocca, 2006 To determine whether LANA2 could be modified by SUMO conjugation, in vitro sumoylation assays using 35 Smethionine-labelled in vitro-translated LANA2 protein ...

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Viruses and sumoylation: recent highlights

Cited by 86 publications

References 54 publications

The Latency-Associated Nuclear Antigen of Kaposi's Sarcoma-Associated Herpesvirus Inhibits Expression of SUMO/Sentrin-Specific Peptidase 6 To Facilitate Establishment of Latency

The Latency-Associated Nuclear Antigen of Kaposi's Sarcoma-Associated Herpesvirus Inhibits Expression of SUMO/Sentrin-Specific Peptidase 6 To Facilitate Establishment of Latency

Regulation of Vaccinia Virus E3 Protein by Small Ubiquitin-Like Modifier Proteins

Covalent modification by SUMO is required for efficient disruption of PML oncogenic domains by Kaposi's sarcoma-associated herpesvirus latent protein LANA2

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