KSHV RTA induces a transcriptional repressor, HEY1 that represses rta promoter

Yada, Kaori; Do, Eunju; Sakakibara, Shuhei; Ohsaki, Eriko; Ito, Emi; Watanabe, Shinya; Ueda, Keiji

doi:10.1016/j.bbrc.2006.04.092

Cited by 21 publications

(29 citation statements)

References 27 publications

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“…We demonstrated that KSHV infection unregulated the level of expression of endogenous Hey1 in B and 293T cells and LANA takes major responsibility for it. Our results showed that Hey1 was degraded by the ubiquitinproteasome system, as indicated by other research (47,48). Ectopic expression of LANA significantly inhibited the degradation of Hey1, in a dose-dependent manner.…”

Section: Discussionsupporting

confidence: 84%

Latency-Associated Nuclear Antigen of Kaposi Sarcoma–Associated Herpesvirus Promotes Angiogenesis through Targeting Notch Signaling Effector Hey1

Wang

Tian

et al. 2014

Cancer Research

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Notch signaling has been implicated in the pathogenesis of Kaposi sarcoma. Kaposi sarcoma is an angioproliferative neoplasm that originates from Kaposi sarcoma-associated herpesvirus (KSHV) infection. Previously, we showed that the KSHV LANA protein can stabilize intracellular Notch in KSHV-infected tumor cells and promote cell proliferation. However, whether Notch signaling functions in pathologic angiogenesis of Kaposi sarcoma remains largely unknown. Hey1, an essential downstream effector of the Notch signaling pathway, has been demonstrated to play a fundamental role in vascular development. In the present study, we performed whole transcriptome, paired-end sequencing on three patient-matched clinical Kaposi sarcoma specimens and their corresponding adjacent stroma samples, with an average depth of 42 million reads per sample. Dll4, Hey1, and HeyL displayed significant upregulation in Kaposi sarcoma. Further verification based on immunohistochemistry analysis demonstrated that Hey1 was indeed highly expressed in Kaposi sarcoma lesions. Using the Matrigel plug assay, we showed that downregulation of Hey1 and g-secretase inhibitor treatment caused dramatic reduction in the formation of new blood vessels in mice. Interestingly, LANA was responsible for the elevated level of Hey1 through inhibition of its degradation. Importantly, Hey1 stabilized by LANA promoted the neoplastic vasculature. Taken together, our data suggest that hijacking of the proangiogenic property of Hey1 by LANA is an important strategy utilized by KSHV to achieve pathologic angiogenesis and that Hey1 is a potential therapeutic target in Kaposi sarcoma. Cancer Res; 74(7); 2026-37. Ó2014 AACR.

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Section: Discussionsupporting

confidence: 84%

Latency-Associated Nuclear Antigen of Kaposi Sarcoma–Associated Herpesvirus Promotes Angiogenesis through Targeting Notch Signaling Effector Hey1

Wang

Tian

et al. 2014

Cancer Research

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“…This suggests that TLE2 is a negative regulator for RTA and plays a role in maintenance of virus latency. Previously, another transcriptional repressor, Hey1, was shown to be upregulated by RTA (77). It is possible that TLE2 expression is responsive to RTA induction upon stimulation within the microenvironment.…”

Section: Resultsmentioning

confidence: 99%

“…It has been shown that RTA can activate its target genes through direct binding with high affinity to RTAresponsive elements (RREs) or in combination with cellular factors, such as RBP-J, Ap-1, C/EBP-␣, Oct-1, and other RTA-interacting proteins previously identified and characterized by yeast two-hybrid screening (37,39,56,62,73,74). During latency, RTA activities are controlled and regulated tightly by viral and host factors (33,77). This facilitates the control of viral gene expression, as well as the maintenance of viral latency.…”

mentioning

confidence: 99%

Cellular Corepressor TLE2 Inhibits Replication-and-Transcription- Activator-Mediated Transactivation and Lytic Reactivation of Kaposi's Sarcoma-Associated Herpesvirus

Liu

Liang

et al. 2010

J Virol

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Replication and transcription activator (RTA) encoded by open reading frame 50 (ORF50) of Kaposi's sarcoma-associated herpesvirus (KSHV) is essential and sufficient to initiate lytic reactivation. RTA activates its target genes through direct binding with high affinity to its responsive elements or by interaction with cellular factors, such as RBP-J, Ap-1, C/EBP-␣, and Oct-1. In this study, we identified transducin-like enhancer of split 2 (TLE2) as a novel RTA binding protein by using yeast two-hybrid screening of a human spleen cDNA library. The interaction between TLE2 and RTA was confirmed by glutathione S-transferase (GST) binding and coimmunoprecipitation assays. Immunofluorescence analysis showed that TLE2 and RTA were colocalized in the same nuclear compartment in KSHV-infected cells. This interaction recruited TLE2 to RTA bound to its recognition sites on DNA and repressed RTA auto-activation and transactivation activity. Moreover, TLE2 also inhibited the induction of lytic replication and virion production driven by RTA. We further showed that the Q (Gln-rich), SP (Ser-Pro-rich), and WDR (Trp-Asp repeat) domains of TLE2 and the Pro-rich domain of RTA were essential for this interaction. RBP-J has been shown previously to bind to the same Pro-rich domain of RTA, and this binding can be subject to competition by TLE2. In addition, TLE2 can form a complex with RTA to access the cognate DNA sequence of the RTA-responsive element at different promoters. Intriguingly, the transcription level of TLE2 could be upregulated by RTA during the lytic reactivation process. In conclusion, we identified a new RTA binding protein, TLE2, and demonstrated that TLE2 inhibited replication and transactivation mediated by RTA. This provides another potentially important mechanism for maintenance of KSHV viral latency through interaction with a host protein.

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“…Recent studies identified additional cellular transcriptional regulators that are targeted by KSHV RTA and ␥HV68 RTA for degradation, including RelA (39) and Hey1 (15,38). Although it is clear that RTA expression is sufficient to induce the ubiquitination and degradation of these transcriptional regulators, it remains an open question whether RTA possesses intrinsic E3 ligase activity toward the substrates identified thus far.…”

Section: Discussionmentioning

confidence: 99%

Murine Gammaherpesvirus 68 Evades Host Cytokine Production via Replication Transactivator-Induced RelA Degradation

Dong

Durakoglugil

et al. 2012

J Virol

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Cytokines play crucial roles in curtailing the propagation and spread of pathogens within the host. As obligate pathogens, gammaherpesviruses have evolved a plethora of mechanisms to evade host immune responses. We have previously shown that murine gammaherpesvirus 68 (␥HV68) induces the degradation of RelA, an essential subunit of the transcriptionally active NF-B dimer, to evade cytokine production. Here, we report that the immediately early gene product of ␥HV68, replication transactivator (RTA), functions as a ubiquitin E3 ligase to promote RelA degradation and abrogate cytokine production. A targeted genomic screen identified that RTA, out of 24 candidates, induces RelA degradation and abolishes NF-B activation. Biochemical analyses indicated that RTA interacts with RelA and promotes RelA ubiquitination, thereby facilitating RelA degradation. Mutations within a conserved cysteine/histidine-rich, putative E3 ligase domain impaired the ability of RTA to induce RelA ubiquitination and degradation. Moreover, infection by recombinant ␥HV68 carrying mutations that diminish the E3 ligase activity of RTA resulted in more robust NF-B activation and cytokine induction than did infection by wild-type ␥HV68. These findings support the conclusion that ␥HV68 subverts early NF-B activation and cytokine production through RTA-induced RelA degradation, uncovering a key function of RTA that antagonizes the intrinsic cytokine production during gammaherpesvirus infection.

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KSHV RTA induces a transcriptional repressor, HEY1 that represses rta promoter

Cited by 21 publications

References 27 publications

Latency-Associated Nuclear Antigen of Kaposi Sarcoma–Associated Herpesvirus Promotes Angiogenesis through Targeting Notch Signaling Effector Hey1

Latency-Associated Nuclear Antigen of Kaposi Sarcoma–Associated Herpesvirus Promotes Angiogenesis through Targeting Notch Signaling Effector Hey1

Cellular Corepressor TLE2 Inhibits Replication-and-Transcription- Activator-Mediated Transactivation and Lytic Reactivation of Kaposi's Sarcoma-Associated Herpesvirus

Murine Gammaherpesvirus 68 Evades Host Cytokine Production via Replication Transactivator-Induced RelA Degradation

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