The human herpes virus 8–encoded viral FLICE inhibitory protein protects against growth factor withdrawal–induced apoptosis via NF-κB activation

Abstract

The human herpes virus 8 (HHV8)-encoded viral FLICE (Fas-associating protein with death domain-like interleukin-1-converting enzyme) inhibitory protein (vFLIP) is believed to protect cells against death receptor-mediated apoptosis. In the present study we demonstrate that expression of HHV8 vFLIP in a growth factor-dependent TF-1 leukemia cell line protects against growth factor withdrawal-induced apoptosis. Unlike vector-expressing cells, those expressing HHV8 vFLIP maintain their mitochondrial membrane potential upon withdrawal from growth factor and also exhibit a block in the activation of caspases. The protective effect of HHV8 vFLIP is associated with its ability to activate the nuclear factor-kappa B (NF-kappaB) pathway and is missing in the vFLIP encoded by equine herpes virus 2 that lacks this activity. Inhibition of the NF-kappaB pathway by IkappaB superrepressor, lactacystin, MG132, arsenic trioxide, and phenylarsine oxide reverse the protection against growth factor withdrawal-induced apoptosis conferred by HHV8 vFLIP. HHV8 vFLIP up-regulates the expression of Bcl-x(L), an antiapoptotic member of the Bcl2 family, which is a known target of the NF-kappaB pathway. Collectively, the above results suggest that HHV8 vFLIP-induced NF-kappaB activation may contribute to cellular transformation seen in association with HHV8 infection by preventing the apoptosis of cells destined to die because of growth factor deprivation.

To be, or not to be: NF-κB is the answer – role of Rel/NF-κB in the regulation of apoptosis

“…The human herpesvirus 8 is linked to Kaposi's sarcoma and primary effusion lymphoma. Its v-FLIP protein suppresses apoptosis triggered by growth factor deprivation by persistently activating the IKK kinase complex thereby inducing expression of Bcl-xL (Liu et al, 2002;Sun et al, 2003). Lastly, gammaherpesviruses establish latent infections in lymphocytes and are implicated in nasopharyngeal carcinoma, Kaposi's sarcoma and B-cell lymphomas.…”

Variability in the Degree of Expression of Phosphorylated IκBα in Chronic Lymphocytic Leukemia Cases With Nodal Involvement

“…Phosphorylated IB␣ has been used as a surrogate for the activation of NF-B, because it constitutes a key step in the release of NF-B subunits and eventual nuclear translocation (17,18). Moreover, a variable response to BCR signaling in CLL cells has been reported previously (33,50,51) and linked to the presence of decreased levels of functionally relevant adhesion molecules, cell-signaling receptors, and 11q22-q23 deletion (16).…”

“…Here we have investigated the correlation of the presence of phosphorylated IB␣ (p-IB␣), a marker of NF-B activation (17,18), with changes in the expression profile and clinical outcome of CLL cases.…”

Induction of spindle cell morphology in human vascular endothelial cells by human herpesvirus 8-encoded viral FLICE inhibitory protein K13

“…However, we have subsequently shown that K13 is a strong inducer of the NF-kB pathway through the activation of the IkB kinase complex and does not function as a caspase-8 inhibitor (Chaudhary et al, 1999;Liu et al, 2002;Matta et al, 2003;Matta and Chaudhary, 2004;Chugh et al, 2005). We and others have further shown that K13 utilizes the NF-kB pathway to promote cellular transformation, cytokine secretion and protection against growth-factor withdrawal-induced apoptosis Sun et al, 2003aSun et al, , b, 2006. We were interested in examining the effect of K13 on vascular endothelial cells, as it is one of the few HHV8-encoded proteins to be expressed in latently infected KS spindle cells and, therefore, is an ideal candidate for inducing spindle cell phenotype in HHV8-infected endothelial cells.…”