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receptors (TLRs), nucleotide-binding oligomerization domain (NOD)-like recep-
tors (NLRs), retinoic acid-inducible gene I (RIG-I)-like receptors (RLR), and cyto-
solic DNA-sensing receptors.
7.5.3.1 KSHV and TLRs
There are ten TLR genes in humans. They are single-pass transmembrane proteins
containing an extracellular leucine-rich repeat (LRR) domain specific for ligand
binding. TLR-1, TLR-2, TLR-4, TLR-5, and TLR-6 are located on the plasma
membrane and sense lipids and lipoproteins, whereas TLR-3, TLR-7, TLR-8, and
TLR-9 are expressed on endosomal membranes to sense nucleic acids. The signal-
ing cascades induced by TLRs include the NF-κB and MAPK pathways, which
activate transcription factors such as activator protein 1 (AP-1) and interferon regu-
latory factor (IRF) via adaptor proteins such as myeloid differentiation factor 88
(MyD88), TIR domain-containing adaptor-inducing IFN- β (TRIF), and TRIF-
related adaptor protein molecule (TRAM). Thus, TLRs activate a diverse range of
intracellular responses and result in the production of inflammatory factors, chemo-
tactic factors, and antiviral factors such as interferon (IFN)-α and IFN-β. KSHV
manipulates each step of TLR signaling to evade it. KSHV RTA or ORF50 down-
regulates TLR2 and TLR4 protein expression and alters their localization on the
plasma membrane [ 198 ]. The adaptor protein TRIF undergoes RTA-mediated deg-
radation through the ubiquitin-proteasome pathway, which blocks the TLR3 path-
way [ 199 ]. MyD88 is also targeted by RTA for degradation via direct interaction
between RTA and MyD88 [ 99 ]. Viral interferon regulatory factors (vIRFs) encoded
by KSHV have three members named vIRF-1, vIRF-2, and vIRF-3. vIRF-1
decreases the phosphorylation and subsequent translocation of IRF3 into the nucleus
upon TLR3 activation [ 200 ].
7.5.3.2 KSHV and NLRs
NLRs consist of another family of PRRs that use LRR scaffold domains to detect
pathogen products in the cytoplasm. NLRs contain a nucleotide-binding oligomer-
ization domain (NOD) and an LRR domain close to the carboxyl terminus. Based
on the domains near the amino terminus, NLRs are divided into two subfamilies.
One subfamily harbors an amino-terminal caspase recruitment domain (CARD) and
is represented by NOD1 and NOD2. Upon ligand activation, the NLRs recruit the
CARD-containing serine-threonine kinase RIPK2. RIPK2 then activates TAK1
kinase, which activates NF-κB by phosphorylating IKK. Another subfamily has a
pyrin domain at its amino terminus and is known as the NLRP family. NLRPs inter-
act with proteins containing other pyrin domains such as PYCARD, which is associ-
ated with pro-caspase1 through the CARD domain. The large complex (termed the
S. Li et al.