112
7.5.4 KSHV-Induced Cellular Metabolic Alterations
Cancer cells rely on aerobic glycolysis for their proliferation, in contrast to normal
cells that generate energy via mitochondrial oxidative phosphorylation. This does
not indicate that mitochondria are useless; however, they are indispensable for ana-
bolic activities such as de novo lipid biosynthesis and glutamine-dependent anaple-
rosis, in what is termed the Warburg effect [ 208 , 209 ]. Therefore, glucose, fatty
acids, and glutamine constitute the cornerstone for tumorigenesis metabolically.
KSHV manipulates these three aspects of metabolism to promote its survival,stress adaptation, and pathogenesis. During latent infection of endothelial cells,
KSHV induces a Warburg effect by enhancing aerobic glycolysis and lactic acid
production while lowering oxygen consumption. Cells will undergo apoptosis
when treated with glycolysis inhibitors, suggesting that this metabolic alteration
Fig. 7.4 Schematic representation of KSHV-induced immune escape and regulation. TLR signal-
ing uses adaptor proteins such as TRIF and MyD88 to mediate signal transduction. RTA can
degrade TRIF and MyD88 via the ubiquitin-proteasome pathway. In addition, RTA downregulates
TLR2 and TLR4 protein expression. Upstream of NF-κB and IRF3, the blockade of adaptor and
receptors of TLR inhibit pro-inflammatory activity. The activity of the RNA sensor RIG-I can be
inhibited by ORF64 through the suppression of K63-linked ubiquitination. The LANA N-terminal
truncated isoform can directly bind the DNA sensor cGAS and disturb the cGAS/cGAMP/STING
pathway. The NLR pathway leads to IL-1 and IL-18 maturation and secretion. ORF63 serves as a
viral homolog of NLRP1 and functions as a dominant negative molecule to block the NLR path-
way. vIRF1 also functions as a dominant negative molecule to block IRF3 phosphorylation and
translocation; furthermore, vIRF1 blocks STING and TBK1 interaction and subsequent IRF3
activation
S. Li et al.