Kaposi's Sarcoma-Associated Herpesvirus-Encoded MicroRNA miR-K12-11 Attenuates Transforming Growth Factor Beta Signaling through Suppression of SMAD5

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) encodes 12 pre-microRNAs (pre-miRNAs). Current studies have shown that these miRNAs are involved in regulation of viral and host gene expression, implicating a role in the maintenance of viral latency and suppression of antiviral innate immunity. However, the functions of these miRNAs remain largely unknown. On the basis of the sequence homology between oncogenic miR-155 and KSHV-encoded miR-K12-11, we hypothesized that miR-K12-11 could attenuate transforming growth factor ␤ (TGF-␤) signaling, facilitating viral infection and tumorigenesis. In the present study, we demonstrated that ectopic expression of miR-K12-11 in Ramos, a TGF-␤-sensitive cell line, downregulated TGF-␤ signaling and facilitated cell proliferation upon TGF-␤ treatment by directly targeting SMAD5, an important mediator in TGF-␤ signaling. In addition, the downregulation of SMAD5 by miR-K12-11 was further confirmed in a de novo KSHV infection system or latently infected KSHV-positive B-lymphoma cell lines. More importantly, repression of miR-K12-11 by a specific sponge inhibitor restored the expression of SMAD5 in both de novo-infected and latently infected cells. Finally, we found that restoration of SMAD5, in addition to the TGF-␤ type II receptor, which was epigenetically silenced by the latent viral protein latencyassociated nuclear antigen, sensitized BC3 cells to the cytostatic effect of TGF-␤ signaling. Taken together, our findings highlight a novel mechanism in which miR-K12-11 downregulates TGF-␤ signaling and suggest that viral miRNAs and proteins may exert a dichotomy regulation in virus-induced oncogenesis by targeting the same signaling pathway.

Inhibition of Kaposi's Sarcoma-Associated Herpesvirus Lytic Replication by HIV-1 Nef and Cellular MicroRNA hsa-miR-1258

“…Among them, several miRNAs regulate viral latency by directly targeting viral genes or indirectly targeting cellular pathways (52, 61-64, 72, 73). KSHV miRNAs also regulate diverse cellular pathways (45,52,(74)(75)(76)(77)(78)(79)(80)(81)(82)(83)(84)(85)(86)(87), which might contribute to the development of KSHV-related malignancies (88). However, how cellular miRNAs regulate KSHV genes and the viral replication program remains to be elucidated.…”

Kaposi's Sarcoma-Associated Herpesvirus Downregulates Transforming Growth Factor β2 To Promote Enhanced Stability of Capillary-Like Tube Formation

“…Importantly, KSHV targets other steps in the TGF-␤ signaling pathway. KSHV miRNAs can target the Smad signaling molecules, which are the downstream effectors of TGF-␤1 (22). T␤RII was also shown to be downregulated in KSHV-infected TIME cells and primary effusion lymphoma cells (23,35).…”

“…Thrombospondin, a potent activator of latent TGF-␤, is targeted by miR-K1, miR-K3-3p, miR-K6-3p, and miR-K11 (21). In addition, SMAD5, a downstream effector of the TGF-␤-pathway, is targeted by miR-K11 (22). miR-K10 has been shown to target T␤RII, inhibiting TGF-␤ signaling (23).…”

Kaposi's Sarcoma-Associated Herpesvirus Encodes a Mimic of Cellular miR-23

“…One major clue to the potential functions of the KSHV miRNAs is the identification of two of the KSHV miRNAs as viral analogs of the cellular miRNAs miR-155 and miR-142-3p (12,14,15). Several additional interactions and functions of the KSHV miRNAs have been identified (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35); however, the overall impact these miRNAs have on host gene expression and their phenotypic consequences remain largely unknown.…”