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phase. p53 controls genomic stability and prevents genomic mutations, and its inac-
tivation promotes cell immortalization. KSHV LANA interacts with both p53 and
pRb, adversely impacting pRb/E2F and p53 transcriptional regulation [ 216 ]. LANA
also serves as a component of the EC5S ubiquitin complex and targets p53 for deg-
radation [ 217 ]. In addition, LANA upregulates Aurora A transcriptional expression,
and Aurora A dramatically enhances the binding affinity of LANA for p53, which
positively controls LANA-mediated p53 degradation [ 218 ]. In addition to LANA,
vIRF1 interacts with p53 through its central DNA-binding domain and inhibits the
transcriptional activity of p53 [ 219 ]. vIRF-3 antagonizes p53 oligomerization and
DNA binding by interacting with p53 and inhibiting p53 phosphorylation on serine
residues S15 and S20 [ 220 ]. K-cyclin, which is uniquely encoded by KSHV, inter-
acts with cyclin-dependent kinase 9 (Cdk9) through its basic domain, which in turn
phosphorylates p53 to regulate its function [ 221 ]. LANA2 (ORF10.5) inhibits the
SUMOylation of p53 by SUMO2, a posttranslational modification of p53 responsi-
ble for virus clearance [ 222 ]. Furthermore, structural proteins such as ORF22, ORF25,
and ORF64 counteract p53-induced apoptosis by suppressing the transactivation of
Fig. 7.5 Schematic representation of KSHV-induced cellular metabolic alterations. KSHV-
infected cells display the Warburg effect: aerobic glycolysis, reduced mitochondrial oxidative
phosphorylation, and glutamine-dependent anaplerosis. KSHV microRNAs target HSPA9, result-
ing in reduced mitochondrial number and EGLN2, which in turn stabilizes HIF-1α. HIF-1α upreg-
ulates pyruvate kinase 2 and delays the generation of Ac-CoA, which enters the TCA cycle. HIF-1α
also helps induce glycolytic genes and promotes the glycolysis process. KSHV induces Myc/Max
and Mondo/Mix heterodimers to upregulate the glutamine transporter SLC1A5 and facilitate glu-
tamine uptake. c-Myc also induces the expression of glutaminase (GLS1), which converts gluta-
mine to glutamate to be utilized for glutaminolysis
S. Li et al.