Viral Inhibitor of Apoptosis vFLIP/K13 Protects Endothelial Cells against Superoxide-Induced Cell Death

Thurau, Mathias; Marquardt, Gaby; Gonin-Laurent, Nathalie; Weinländer, Kristina; Naschberger, Elisabeth; Jochmann, Ramona; Alkharsah, Khaled R.; Schulz, Thomas F.; Thome, Margot; Neipel, Frank; Stürzl, Michael

doi:10.1128/jvi.00629-08

Cited by 44 publications

(47 citation statements)

References 76 publications

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“…K13 has been previously described as an NF-B activator (9, 11,19,57,60). The data shown here confirmed that K13 is the strongest NF-B activator of all HHV-8 genes, with an average fc of 3.9 (Fig.…”

Section: Resultssupporting

confidence: 75%

A Systems Biology Approach To Identify the Combination Effects of Human Herpesvirus 8 Genes on NF-κB Activation

Konrad

Wies

Thurau

et al. 2009

J Virol

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Section: Resultssupporting

confidence: 75%

A Systems Biology Approach To Identify the Combination Effects of Human Herpesvirus 8 Genes on NF-κB Activation

Konrad

Wies

Thurau

et al. 2009

J Virol

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“…The resulting IκB phosphorylation displaces IκB from NF-κB, releasing the active transcription factor to the nucleus, where it activates a large panel of antiapoptotic and proinflammatory genes. Expression of v-FLIP in spindle cells thus not only can extend their lifespan (142,143) but also can explain, at least in part, the inflammatory phenotype of KS lesions. NF-κB activation by v-FLIP expression in endothelial cells has also been linked to a third phenotype relevant to KS - the dramatic rearrangement of the cytoskeleton that gives the cells their characteristic spindle shape (78,144).…”

Section: How Does Kshv Infection Predispose To Ks?mentioning

confidence: 99%

KSHV and the pathogenesis of Kaposi sarcoma: listening to human biology and medicine

Ganem¹

2010

J. Clin. Invest.

336

380

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“…vFLIP potently prevents the accumulation of superoxide in endothelial cells and consequently prevents apoptosis induced by oxidative stress (90). vFLIP upregulates the expression of manganese superoxide dismutase (MnSOD) through activation of the transcription factor NF-B (90).…”

Section: Fig 11mentioning

confidence: 99%

Kaposi's Sarcoma-Associated Herpesvirus Induces Nrf2 Activation in Latently Infected Endothelial Cells through SQSTM1 Phosphorylation and Interaction with Polyubiquitinated Keap1

Gjyshi

Flaherty

Veettil

et al. 2015

J Virol

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Nuclear factor erythroid 2-related factor 2 (Nrf2), the cellular master regulator of the antioxidant response, dissociates from its inhibitor Keap1 when activated by stress signals and participates in the pathogenesis of viral infections and tumorigenesis. Early during de novo infection of endothelial cells, KSHV induces Nrf2 through an intricate mechanism involving reactive oxygen species (ROS) and prostaglandin E2 (PGE2). When we investigated the Nrf2 activity during latent KSHV infection, we observed increased nuclear serine-40-phosphorylated Nrf2 in human KS lesions compared to that in healthy tissues. Using KSHV long-term-infected endothelial cells (LTC) as a cellular model for KS, we demonstrated that KSHV infection induces Nrf2 constitutively by extending its half-life, increasing its phosphorylation by protein kinase C (PKC) via the infection-induced cyclooxygenase-2 (COX-2)/PGE2 axis and inducing its nuclear localization. Nrf2 knockdown in LTC decreased expression of antioxidant genes and genes involved in KS pathogenesis such as the NAD(P)H quinone oxidase 1 (NQO1), gamma glutamylcysteine synthase heavy unit (␥GCSH), the cysteine transporter (xCT), interleukin 6 (IL-6), and vascular endothelial growth factor A (VEGF-A) genes. Nrf2 activation was independent of oxidative stress but dependent on the autophagic protein sequestosome-1 (SQSTM1; p62). SQSTM1 levels were elevated in LTC, a consequence of protein accumulation due to decreased autophagy and Nrf2-mediated transcriptional activation. SQSTM1 was phosphorylated on serine-351 and -403, while Keap1 was polyubiquitinated with lysine-63-ubiquitin chains, modifications known to increase their mutual affinity and interaction, leading to Keap1 degradation and Nrf2 activation. The latent KSHV protein Fas-associated death domain-like interleukin-1␤-converting enzyme-inhibitory protein (vFLIP) increased SQSTM1 expression and activated Nrf2. Collectively, these results demonstrate that KSHV induces SQSTM1 to constitutively activate Nrf2, which is involved in the regulation of genes participating in KSHV oncogenesis. IMPORTANCEThe transcription factor Nrf2 is activated by stress signals, including viral infection, and responds by activating the transcription of cytoprotective genes. Recently, Nrf2 has been implicated in oncogenesis and was shown to be activated during de novo KSHV infection of endothelial cells through ROS-dependent pathways. The present study was undertaken to determine the mechanism of Nrf2 activation during prolonged latent infection of endothelial cells, using an endothelial cell line latently infected with KSHV. We show that Nrf2 activation was elevated in KSHV latently infected endothelial cells independently of oxidative stress but dependent on the autophagic protein sequestosome-1 (SQSTM1), which was involved in the degradation of the Nrf2 inhibitor Keap1. Furthermore, our results indicated that the KSHV latent protein vFLIP participates in Nrf2 activation. This study suggests that KSHV hijacks the host's autophagic protein SQS...

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Viral Inhibitor of Apoptosis vFLIP/K13 Protects Endothelial Cells against Superoxide-Induced Cell Death

Abstract: Human herpesvirus 8 (HHV-8) is the etiological agent of Kaposi's sarcoma (KS).

Cited by 44 publications

References 76 publications

A Systems Biology Approach To Identify the Combination Effects of Human Herpesvirus 8 Genes on NF-κB Activation

A Systems Biology Approach To Identify the Combination Effects of Human Herpesvirus 8 Genes on NF-κB Activation

KSHV and the pathogenesis of Kaposi sarcoma: listening to human biology and medicine

Kaposi's Sarcoma-Associated Herpesvirus Induces Nrf2 Activation in Latently Infected Endothelial Cells through SQSTM1 Phosphorylation and Interaction with Polyubiquitinated Keap1

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