KSHV vCyclin counters the senescence/G1 arrest response triggered by NF-κB hyperactivation

Abstract

Many oncogenic viruses activate NF-κB as a part of their replicative cycles. We have shown recently that persistent and potentially oncogenic activation of NF-κB by the human T-lymphotropic virus 1 (HTLV-1) oncoprotein Tax immediately triggers a host senescence response mediated by cyclin-dependent kinase inhibitors: p21CIP1/WAF1 (p21) and p27Kip1 (p27) Here we demonstrate that RelA/NF-κB activation by Kaposi sarcoma herpesvirus (KSHV) latency protein vFLIP also leads to p21/p27 up-regulation and G1 cell cycle arrest. Remarkably, KSHV vCyclin, another latency protein co-expressed with vFLIP from a bicistronic latency-specific mRNA, was found to prevent the senescence and G1 arrest induced by HTLV-1 Tax and vFLIP respectively. This is due to the known ability of vCyclin/CDK6 complex to resist p21 and p27 inhibition and cause p27 degradation23. In KSHV-transformed BCBL-1 cells, sustained vFLIP expression with shRNA-mediated vCyclin depletion resulted in G1 arrest. The functional interdependence of vFLIP and vCyclin explains why they are co-translated from the same viral mRNA. Importantly, deregulation of the G1 cyclin-dependent kinase can facilitate chronic IKK/NF-κB activation.

Generation of a KSHV K13 deletion mutant for vFLIP function study

“…For KSHV‐encoded miR‐K12‐1‐5p and miR‐K12‐1‐3p, the underlying reasons include that as the nearest downstream gene, the deletion K13 CDS may influence the pre‐miRNA folding and accessibility to Drosha, which lead to the expression levels of the derived mature miRNAs . For the upstream vCyclin encoded by ORF72, since the functions of vFLIP and vCyclin are interdependence, vFLIP deletion may result in the up‐regulation of vCyclin mRNA . Besides, the dominant strategy for vFLIP expression in latency is bicistronic ORF72/71 mRNA rather than monocistronic ORF71 RNA in latent PEL cells, while translation efficiency could be influenced by RNA structures.…”

“…37 For the upstream vCyclin encoded by ORF72, since the functions of vFLIP and vCyclin are interdependence, vFLIP deletion may result in the up-regulation of vCyclin mRNA. 38 Besides, the dominant strategy for vFLIP expression in latency is bicistronic ORF72/71 mRNA rather than monocistronic ORF71 RNA in latent PEL cells, 39 while translation efficiency could be influenced by RNA structures. Thus, the deletion of vFLIP may change the structure of bicistronic ORF72/71 mRNA, which could explain the alteration of vCyclin mRNA expression.…”

Oncogenic spiral by infectious pathogens: Cooperation of multiple factors in cancer development

“…vFLIP also induces G1 arrest/senescence in HeLa cells through hyperactivation of NF‐κB that is reminiscent of Tax‐mediated senescence. In this setting, v‐cyclin prevents cell cycle arrest by vFLIP . It is suggested that these two proteins work in concert to accelerate the transformation of KSHV‐infected cells.…”

“…In this setting, v-cyclin prevents cell cycle arrest by vFLIP. 56 It is suggested that these two proteins work in concert to accelerate the transformation of KSHV-infected cells.…”

KSHV viral cyclin interferes with T-cell development and induces lymphoma through Cdk6 and Notch activation in vivo

“…23,25,[27][28][29] In addition, vcyclin has recently been shown to promote KSHV-induced postconfluent growth and transformation in rat mesenchymal cells, 30 and to counteract the G1-arrest triggered by another latent viral protein, vFLIP, through NF-kB hyperactivation. 31 However, vcyclin not only promotes proliferation, as its overexpression also induces a p53-dependent growth arrest and apoptosis, 26,[32][33][34] activates the DNA damage response, 32 and increases autophagy. 35 The in vivo function of v-cyclin in the lymphocyte compartment has previously been addressed by expressing it as a transgene under the immunoglobulin heavy chain promoter/enhancer Em in a mixed CBA/C57BL/6 mouse background (Em-v-cyclin mice).…”