From the targets identified to date (Table 1, Figure 1) it is apparent that viral miRNAs play an important role in immune evasion by inhibiting immune surveillance and extending the life of the infected host cell. Table 1 Immunomodulatory viral miRNAs.
In a surprising twist, by systematic functional testing of EBV and KSHV miRNAs, Nachmani et al. later showed that EBV as well as KSHV also express miRNAs with the ability to suppress MICB expression (Nachmani et al., 2009).
The major histocompatibility complex class I-related chain B (MICB) is a stress-induced protein recognized by the NKG2D receptor on NK-cells and CD8+ T-lymphocytes. Interaction between MICB and NKG2D generates a cytolytic response by NK- and T-cells. Nachmani et.al. demonstrated that the 3'UTR of MICB is targeted by EBV miRNA, BART2-5p and by the KSHV miRNA, miR-K12-7.
Here, we show functional conservation among diverse microRNAs derived from different herpesviruses, including HCMV, Kaposi's sarcoma-associated herpesvirus (KSHV), and Epstein-Barr virus (EBV), in their ability to directly target MICB mRNA and reduce its expression. Although the various viral microRNAs share no sequence homology, they are functionally similar and target MICB at different yet adjacent sites during authentic viral infection.
Flow analysis of 293 cells transfected with KSHV miRNAs revealed miR-K12-7 inhibited MICB protein expression, but mRNA levels were not significantly changed. MICB is a surface marker that can be upregulated by viral infection and recognized by NK cells.
Our dataset also confirmed 12 out of 29 validated KSHV miRNA targets with expression in our dataset(>40%). Confirmed interactions include those with BACH1, FOS, CDKN1A(p21), TNFRSF12A(TWEAKR), RAD21 and RBL2 mRNAs, whose regulation had previously been validated at the level of protein expression. A list summarizing the recovery of previously published targets of the KSHV and EBV miRNAs is presented in Table S9. NIHMS333942-supplement-01 Table S9 Recovery of previously published targets for KSHV or EBV miRNAs.