NEMO Is Essential for Kaposi's Sarcoma-Associated Herpesvirus-Encoded vFLIP K13-Induced Gene Expression and Protection against Death Receptor-Induced Cell Death, and Its N-Terminal 251 Residues Are Sufficient for This Process

Abstract

IMPORTANCEKaposi's sarcoma-associated herpesvirus-encoded vFLIP K13 is believed to protect virally infected cells against death receptorinduced apoptosis and to activate the NF-B pathway by binding to adaptor protein NEMO/IKK␥. However, whether K13 can also induce gene expression independently of NEMO and the minimum region of NEMO that is sufficient for supporting K13-induced NF-B remain to be delineated. Furthermore, the contribution of NEMO and NF-B to the protective effect of K13 against death receptor-induced apoptosis is not clear. We demonstrate that NEMO is required for modulation of K13-induced genes and its N-terminal 251 amino acids are sufficient for supporting K13-induced NF-B. The ability of K13 to protect against TNF-␣-induced cell death is critically dependent on its ability to interact with NEMO and activate NF-B. Our results suggest that K13-based gene therapy approaches may have utility for the treatment of patients with NEMO mutations and immunodeficiency.

Azidothymidine Sensitizes Primary Effusion Lymphoma Cells to Kaposi Sarcoma-Associated Herpesvirus-Specific CD4+ T Cell Control and Inhibits vIRF3 Function

“…Such KSHV gene products would include vFLIP which can inhibit killing via Fas [27,28] and a second receptor mediated killing mechanism, TNF-α [29]. Consistent with these studies we found that expression of vFLIP in BJAB cells inhibited killing by anti-Fas antibody and TRAIL.…”

Diverse mechanisms evolved by DNA viruses to inhibit early host defenses

“…The HCMV UL36 gene encodes a multi-functional cell death suppressor, denoted viral inhibitor of caspase-8 activation (vICA) protein, which binds pro-caspase-8 and inhibits its activation by interference with its recruitment to DISC (McCormick et al, 2010). Similar vFLIPs from other herpesviruses have also been found, including herpesvirus saimiri protein ORF71 (Glykofrydes et al, 2000), equine herpesvirus 2 (EHV-2) protein E8 (Hu et al, 1997), and HHV-8 protein K13 (Tolani et al, 2014). …”

Immune control of oncogenic γ-herpesviruses

“…KSHV encodes several anti-apoptosis factors, including vBcl-2 [74], vFLIP [75], vIAP [74], K1 [76,77], vIRF4 [78], LANA [79] and miR-K10a [80]. Together, these viral factors target both the extrinsic and intrinsic apoptosis pathways.…”