A Unique SUMO-2-Interacting Motif within LANA Is Essential for KSHV Latency

Cai, Qiliang; Shen, Cai; Zhu, Changlian; Verma, Suhbash C.; Choi, Ji-Young; Robertson, Erle S.

doi:10.1371/journal.ppat.1003750

Cited by 59 publications

(97 citation statements)

References 65 publications

(92 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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). Our results showed that LANA bound directly to the SENP6 promoter and repressed its activity, inhibiting SENP6 expression at both the RNA and protein levels.…”

Section: Discussionmentioning

confidence: 99%

“…As a SUMO-specific protease, SENP6 is able to deconjugate SUMO2/3, but not SUMO1, from substrates, especially the poly-SUMO chain (40). Additionally, LANA was reported to be sumoylated by both SUMO1 and SUMO2/3 (35). Thus, we hypothesized that SENP6 might reduce LANA by desumoylation.…”

mentioning

confidence: 99%

“…In addition, LANA is methylated at arginine 20 by protein arginine methyltransferase 1 (PRMT1) to enhance histone binding (34). Recent studies suggested that LANA may be subjected to sumoylation and be involved in the regulation of sumoylation (35). LANA can function as a SUMO E3 ligase, a SUMO-binding protein, and a sumoylated protein (27,35).…”

mentioning

confidence: 99%

“…Recent studies suggested that LANA may be subjected to sumoylation and be involved in the regulation of sumoylation (35). LANA can function as a SUMO E3 ligase, a SUMO-binding protein, and a sumoylated protein (27,35). Recently, LANA SIM (SUMOinteracting motif of LANA) has been reported to interact with protein complexes involved in cell cycle (particular mitosis), DNA unwinding and replication, and premRNA/mRNA processing (36).…”

mentioning

confidence: 99%

See 3 more Smart Citations

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

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

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

View full text Add to dashboard Cite

show abstract

“…LANA-1 plays an important role in repressing lytic genes by binding to and repressing the ORF50/RTA promoter (13,14). It was recently found that LANA-1 recruits the host transcriptional repressor KAP1 (Krüppel-associated box [KRAB]-associated protein 1; also known as TRIM28 or TIF1␤), which repressed the ORF50 promoter (15,16). However, the location, mechanism, and dynamics of LANA-1/KAP1 binding to the ORF50 promoter have yet to be investigated.…”

mentioning

confidence: 99%

Activated Nrf2 Interacts with Kaposi's Sarcoma-Associated Herpesvirus Latency Protein LANA-1 and Host Protein KAP1 To Mediate Global Lytic Gene Repression

Gjyshi

Roy

Dutta

et al. 2015

J Virol

View full text Add to dashboard Cite

Kaposi's sarcoma-associated herpesvirus (KSHV) is etiologically associated with Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman's disease. We have previously shown that KSHV utilizes the host transcription factor Nrf2 to aid in infection of endothelial cells and oncogenesis. Here, we investigate the role of Nrf2 in PEL and PEL-derived cell lines and show that KSHV latency induces Nrf2 protein levels and transcriptional activity through the COX-2/PGE2/EP4/PKC axis. Next-generation sequencing of KSHV transcripts in the PEL-derived BCBL-1 cell line revealed that knockdown of this activated Nrf2 results in global elevation of lytic genes. Nrf2 inhibition by the chemical brusatol also induces lytic gene expression. Both Nrf2 knockdown and brusatol-mediated inhibition induced KSHV lytic reactivation in BCBL-1 cells. In a series of follow-up experiments, we characterized the mechanism of Nrf2-mediated regulation of KSHV lytic repression during latency. Biochemical assays showed that Nrf2 interacted with KSHV latency-associated nuclear antigen 1 (LANA-1) and the host transcriptional repressor KAP1, which together have been shown to repress lytic gene expression. Promoter studies showed that although Nrf2 alone induces the open reading frame 50 (ORF50) promoter, its association with LANA-1 and KAP1 abrogates this effect. Interestingly, LANA-1 is crucial for efficient KAP1/Nrf2 association, while Nrf2 is essential for LANA-1 and KAP1 recruitment to the ORF50 promoter and its repression. Overall, these results suggest that activated Nrf2, LANA-1, and KAP1 assemble on the ORF50 promoter in a temporal fashion. Initially, Nrf2 binds to and activates the ORF50 promoter during early de novo infection, an effect that is exploited during latency by LANA-1-mediated recruitment of the host transcriptional repressor KAP1 on Nrf2. Cell death assays further showed that Nrf2 and KAP1 knockdown induce significant cell death in PEL cell lines. Our studies suggest that Nrf2 modulation through available oral agents is a promising therapeutic approach in the treatment of KSHV-associated malignancies. IMPORTANCEKS and PEL are aggressive KSHV-associated malignancies with moderately effective, highly toxic chemotherapies. Other than ganciclovir and alpha interferon (IFN-␣) prophylaxis, no KSHV-associated chemotherapy targets the underlying infection, a major oncogenic force. Hence, drugs that selectively target KSHV infection are necessary to eradicate the malignancy while sparing healthy cells. We recently showed that KSHV infection of endothelial cells activates the transcription factor Nrf2 to promote an environment conducive to infection and oncogenesis. Nrf2 is modulated through several well-tolerated oral agents and may be an important target in KSHV biology. Here, we investigate the role of Nrf2 in PEL and demonstrate that Nrf2 plays an important role in KSHV gene expression, lytic reactivation, and cell survival by interacting with the host transcriptional repressor KAP1 and the viral latency-...

show abstract

SUMOylation in Viral Replication and Antiviral Defense

Fan

Zhang

et al. 2022

Advanced Science

View full text Add to dashboard Cite

SUMOylation is a ubiquitination-like post-translational modification that plays an essential role in the regulation of protein function. Recent studies have shown that proteins from both RNA and DNA virus families can be modified by SUMO conjugation, which facilitates viral replication. Viruses can manipulate the entire process of SUMOylation through interplay with the SUMO pathway. By contrast, SUMOylation can eliminate viral infection by regulating host antiviral immune components. A deeper understanding of how SUMOylation regulates viral proteins and cellular antiviral components is necessary for the development of effective antiviral therapies. In the present review, the regulatory mechanism of SUMOylation in viral replication and infection and the antiviral immune response, and the consequences of this regulation for viral replication and engagement with antiviral innate immunity are summarized. The potential therapeutic applications of SUMOylation in diseases caused by viruses are also discussed.

show abstract

A Unique SUMO-2-Interacting Motif within LANA Is Essential for KSHV Latency

Cited by 59 publications

References 65 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

Activated Nrf2 Interacts with Kaposi's Sarcoma-Associated Herpesvirus Latency Protein LANA-1 and Host Protein KAP1 To Mediate Global Lytic Gene Repression

SUMOylation in Viral Replication and Antiviral Defense

Contact Info

Product

Resources

About