Abstract
The two human lymphotrophic γ-herpesviruses, Kaposi's sarcoma herpesvirus (KSHV) and Epstein-Barr virus (EBV), are a recognized cause of human cancer, encoding multiple miRs that are major players in carcinogenesis. Previously, we discovered that EBV-encoded miRs transfer between infected B and T lymphocytes. To further explore the biological significance of the spreading of γ-herpesvirus-encoded miRs on carcinogenesis, we focused on KSHV-miR-K12-11 (miR-K12-11) that is unique in having an identical seed sequence with the oncomiR hsa-miR-155, implicated in B cell lymphomas development. Here, we show for the first time that miR-K12-11 transfers in vitro from KSHV-infected BCBL-1 and BC-1 lymphoma lines to T cells. The transferred miR-K12-11 is active in the adopting T cells and binds its canonical target, the 3′-UTR of BACH1. Importantly, we show that the transfer of miR-K12-11 from BCBL-1 to Jurkat cells correlates with inhibition of the innate type-I interferons response to viral dsRNAs downstream of IKKε, a validated miR-K12-11 target. Finally, we show that miR-K12-11 spreading is not reduced by blocking the classical ceramide-dependent exosome secretion pathway. In summary, we report for the first time that intercellular viral oncomiR spreading is an additional mechanism employed by KSHV to inhibit host anti-viral immunity and consequently promote oncogenesis.
Highlights
The viral agents Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) are the two lymphotrophic γ-herpesviruses that have evolved to maintain persistent latent infections in humans
While BC-1 is dually-infected with KSHV and EBV [15], BCBL-1 is infected by KSHV alone [16]
We tested the expression levels of miR-K12-11, the oncogenic hsa-miR-155 orthologue, in these two celllines by qRTPCR. We found that both BCBL-1 and BC-1 cells expressed very high levels of the mature miR-K12-11 normalized to the KSHV-free/EBV-infected B721.221 cells (Figure 1A)
Summary
The viral agents Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) are the two lymphotrophic γ-herpesviruses that have evolved to maintain persistent latent infections in humans. Latent infection with γ-herpesviruses are associated with the expression of non-coding RNAs from the viral genome, including miR precursors predicted to target many host genes [3]. The KSHV and EBV genomes contains 12 and 25 validated miR loci, respectively, which encode for multiple mature miRs [3]. EBV- and KSHV-encoded miRs do not share significant sequence homology they target a large number of similar genes [4]. In plants and invertebrates small non coding dsRNAs have been shown to spread systemically and transmit molecular information such as gene silencing [4].
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