Epstein-Barr virus (EBV)-encoded small RNAs (EBERs) are polyA-, non-coding RNAs that are expressed abundantly in all forms of cells latently infected with EBV. EBERs (
EBER1 and
EBER2) contribute to the clonal proliferation of EBV-negative
Burkitt's lymphoma (BL) cells in soft
agar, tumorigenicity in SCID mice, up-regulation of the bcl-2
oncoprotein, resistance to apoptosis, and maintenance of malignant phenotypes in BL cells. EBERs induce the expression of
interleukin (IL)-10 in BL cells,
insulin-like growth factor 1 (
IGF-I) in gastric and
nasopharyngeal carcinoma cells,
IL-9 in T cells, and
IL-6 in lymphoblastoid cell lines. Additionally, each of these
cytokines acts as an autocrine
growth factor. In BL cells, EBERs bind the
double-stranded RNA-activated
protein kinase PKR, inhibit its phosphorylation, and thereby prevent IFN-alpha-mediated apoptosis. In epithelial cells, EBERs confer resistance to Fas-mediated apoptosis by blocking PKR activity. EBERs form complexes with PKR,
ribosomal protein L22, lupus erythematosis-associated
antigen (La), and
retinoic acid-inducible gene I (RIG-I). In BL cells, EBERs activate RIG-I signaling and induce the expression of type-I IFNs and
interferon stimulated genes (ISGs) through the activation of RIG-I substrates,
nuclear factor-kappa B (
NF-kappaB), and
IFN regulatory factor 3 (IRF-3), and anti-inflamatory
cytokine IL-10 through IRF-3 but not
NF-kappaB signaling. EBERs also play critical roles in the growth transformation of B lymphocytes. Although
EBER1 and
EBER2 exhibit similarities in their primary (54%) and secondary structures, recent findings have shown that recombinant EBVs carrying only the
EBER2 gene play a greater role in the growth transformation of B lymphocytes than EBVs carrying only the
EBER1 gene. Thus, EBERs play multiple roles in various cell types, and we present a model that highlights the functions of EBERs in EBV-mediated
oncogenesis in BL cells.