Kaposi's Sarcoma-Associated Herpesvirus-Encoded Latency-Associated Nuclear Antigen Reduces Interleukin-8 Expression in Endothelial Cells and Impairs Neutrophil Chemotaxis by Degrading Nuclear p65

Li, Xiaofan; Liang, Deguang; Lin, Xianzhi; Robertson, Erle S.; Lan, Ke

doi:10.1128/jvi.00733-11

Cited by 27 publications

(28 citation statements)

References 102 publications

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“…It was reported previously that ␥HV68 and KSHV LANA (ORF73), an essential latent gene product, induce nuclear RelA degradation and inhibit NF-B activation (20,28). However, in our reporter assay-based screen, ␥HV68 LANA failed to significantly inhibit RelA-mediated NF-B activation, presumably due to the low dose of plasmid (50 ng) that we used.…”

Section: Discussioncontrasting

confidence: 48%

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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Section: Discussioncontrasting

confidence: 48%

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

Dong

Durakoglugil

et al. 2012

J Virol

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“…The negative control was a mus-scrambled sequence, namely 5 0 -GTTCTCCGAACGTGTCACGT 0 . The 293T cells were transiently transfected using the polyethyleneimine method as described previously, with minor modifications (31). LANA, Hey1, and shHey1 were packaged into lentivirus following the manufacturer's protocol.…”

Section: Plasmids Shrna and Transfectionmentioning

confidence: 99%

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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“…In contrast, mLANA stabilizes Myc through heterotypic polyubiquitination, increasing Myc transcriptional activity and promoting virus-driven lymphoproliferation (8). A parallel exists with kLANA, as that protein has also been shown to mediate degradative ubiquitination of NF-B (6). Interestingly, evolutionary differences exist, since kLANA also targets Myc, leading to its increased stability, but in contrast to mLANA, not through E3 ligase activity on Myc but indirectly via interaction with glycogen synthase kinase 3 (GSK-3) (26,27).…”

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confidence: 99%

“…Examples are latency-associated nuclear antigen (LANA) of Kaposi's sarcoma-associated herpesvirus (KSHV) (5,6) and murid herpesvirus 4 (MuHV-4) (7,8) (mLANA and kLANA, respectively), BZLF1 of Epstein-Barr virus (EBV) (9), Vif of human immunodeficiency virus type 1 (HIV-1) (10)(11)(12), and E4orf6/E1B55K of adenovirus (13). Several studies have shown that these viral proteins target multiple cellular substrates for polyubiquitination.…”

mentioning

confidence: 99%

Latency-Associated Nuclear Antigen E3 Ubiquitin Ligase Activity Impacts Gammaherpesvirus-Driven Germinal Center B Cell Proliferation

Cerqueira

Tan

et al. 2016

J Virol

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Viruses have evolved mechanisms to hijack components of cellular E3 ubiquitin ligases, thus modulating the ubiquitination pathway. However, the biological relevance of such mechanisms for viral pathogenesis in vivo remains largely unknown. Here, we utilized murid herpesvirus 4 (MuHV-4) infection of mice as a model system to address the role of MuHV-4 latency-associated nuclear antigen (mLANA) E3 ligase activity in gammaherpesvirus latent infection. We show that specific mutations in the mLANA SOCS box (V199A, V199A/L202A, or P203A/P206A) disrupted mLANA's ability to recruit Elongin C and Cullin 5, thereby impairing the formation of the Elongin BC/Cullin 5/SOCS (EC 5 S mLANA ) complex and mLANA's E3 ligase activity on host NF-B and Myc. Although these mutations resulted in considerably reduced mLANA binding to viral terminal repeat DNA as assessed by electrophoretic mobility shift assay (EMSA), the mutations did not disrupt mLANA's ability to mediate episome persistence. In vivo, MuHV-4 recombinant viruses bearing these mLANA SOCS box mutations exhibited a deficit in latency amplification in germinal center (GC) B cells. These findings demonstrate that the E3 ligase activity of mLANA contributes to gammaherpesvirus-driven GC B cell proliferation. Hence, pharmacological inhibition of viral E3 ligase activity through targeting SOCS box motifs is a putative strategy to control gammaherpesvirus-driven lymphoproliferation and associated disease. A s obligatory intracellular parasites, viruses have evolved mechanisms to modulate ubiquitination, which is an essential regulatory mechanism in eukaryotes, controlling a wide range of cellular pathways. Ubiquitination occurs through a threeenzyme cascade involving an E1 ubiquitin-activating enzyme, an E2 ubiquitin-conjugating enzyme, and an E3 ubiquitin ligase enzyme (1). E3 ligases bind to the E2-ubiquitin intermediate and the substrate, catalyzing the transfer of ubiquitin to the substrate target lysine. Many E3 ligases have been described, such as Cullin 5-RING E3 ligases (CRL5), also known as Elongin BC/Cullin 5/SOCS (EC 5 S) E3 ligases. They are multisubunit complexes containing a scaffold protein (Cullin 5) attached to a RING finger protein (Rbx) (Cullin 5-Rbx module), an adaptor heterodimer (Elongin B/C), and a substrate recognition protein (suppressor of cytokine signaling [SOCS] box protein). The last component bridges the substrate of ubiquitination and the E3 ligase complex by interacting with Elongin B/C and Cullin 5 through a SOCS box motif (2-4). IMPORTANCE The gammaherpesviruses Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) cause lifelong persistent infection and play causative roles in several human malignancies. Colonization of B cells is crucial for virusCertain viruses encode proteins with SOCS box motifs to hijack the components of cellular E3 ligases, thus modulating the ubiquitination pathway. Examples are latency-associated nuclear antigen (LANA) of Kaposi's sarcoma-associated herpesvirus (KSHV) (5, 6) and murid he...

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Kaposi's Sarcoma-Associated Herpesvirus-Encoded Latency-Associated Nuclear Antigen Reduces Interleukin-8 Expression in Endothelial Cells and Impairs Neutrophil Chemotaxis by Degrading Nuclear p65

Cited by 27 publications

References 102 publications

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

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

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

Latency-Associated Nuclear Antigen E3 Ubiquitin Ligase Activity Impacts Gammaherpesvirus-Driven Germinal Center B Cell Proliferation

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