KSHV miRNAs Decrease Expression of Lytic Genes in Latently Infected PEL and Endothelial Cells by Targeting Host Transcription Factors

Plaisance-Bonstaff, Karlie; Choi, Hong Seok; Beals, Tyler; Krueger, Brian J.; Boss, Isaac W.; Haecker, Irina; Hu, Jianhong; Renne, Rolf

doi:10.3390/v6104005

Cited by 39 publications

(39 citation statements)

References 65 publications

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“…MiR-K3 has been reported to maintain viral latency by targeting nuclear factor I/B, MYB, C/EBPα and Ets-1 [19, 39]. In addition, we have found that miR-K3 directly targets GRK2/CXCR2/AKT pathway to promote migration and invasion of endothelial cells [40].…”

Section: Resultsmentioning

confidence: 99%

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A KSHV microRNA enhances viral latency and induces angiogenesis by targeting GRK2 to activate the CXCR2/AKT pathway

et al. 2016

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Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma (KS), primary effusion lymphoma (PEL) and multicentric Castleman's disease (MCD). Most tumor cells in these malignancies are latently infected by KSHV. Thus, viral latency is critical for the development of tumor and induction of tumor-associated angiogenesis. KSHV encodes more than two dozens of miRNAs but their roles in KSHV-induced angiogenesis remains unknown. We have recently shown that miR-K12-3 (miR-K3) promoted cell migration and invasion by targeting GRK2/CXCR2/AKT signaling (PLoS Pathog, 2015;11(9):e1005171). Here, we further demonstrated a role of miR-K3 and its induced signal pathway in KSHV latency and KSHV-induced angiogenesis. We found that overexpression of miR-K3 not only promoted viral latency by inhibiting viral lytic replication, but also induced angiogenesis. Further, knockdown of GRK2 inhibited KSHV replication and enhanced KSHV-induced angiogenesis by enhancing the CXCR2/AKT signals. As a result, blockage of CXCR2 or AKT increased KSHV replication and decreased angiogenesis induced by PEL cells in vivo. Finally, deletion of miR-K3 from viral genome reduced KSHV-induced angiogenesis and increased KSHV replication. These findings indicate that the miR-K3/GRK2/CXCR2/AKT axis plays an essential role in KSHV-induced angiogenesis and promotes KSHV latency, and thus may be a potential therapeutic target of KSHV-associated malignancies.

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Section: Resultsmentioning

confidence: 99%

“…Furthermore, miR-K3 contributes to the maintenance of latency by decreasing RTA expression via down-regulation of MYB, C/EBPα and Ets-1 [39]. We have recently revealed that miR-K3 directly targets G protein-coupled receptor kinase 2 (GRK2) to promote endothelial cell migration and invasion by activating CXCR2/AKT signaling [40].…”

Section: Introductionmentioning

confidence: 99%

A KSHV microRNA enhances viral latency and induces angiogenesis by targeting GRK2 to activate the CXCR2/AKT pathway

et al. 2016

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“…During differentiation of CD34+ progenitor cells to a myeloid lineage that supports productive infection, the levels of these miRNAs drop indicating that both viral and host miRNAs regulate viral latency and reactivation. Viral miRNAs also regulate cellular pathways to help maintain viral latency, as demonstrated for KSHV, where viral miRNAs mediate the repression of the Replication and Transcription Activator (RTA) [55,56] and target the NF-kB pathway [57,58]. By both direct and indirect repression of key viral transactivators, viral and cellular miRNAs thus inhibit lytic replication and aid both the establishment and maintenance of viral latency.…”

Section: Micrornas In Latency and Reactivationmentioning

confidence: 96%

Small RNAs growing tall: miRNAs as drug targets in herpesvirus infections

L’Hernault

Dölken

2015

Current Opinion in Virology

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“…Viral miRNAs have also been shown to be important for gammaherpesvirus reactivation from latency, typically by playing inhibitory roles. This is mediated either by direct repression of Rta or Zta, viral transcription factors that initiate lytic cycle replication, or indirectly through repression of the pathways leading to transcription of these factors (60)(61)(62)(63)(64). The KSHV homolog of miR-155, miR-K12-11, specifically was shown to inhibit Rta by inhibiting transcription factors known to activate the Rta promoter (64).…”

Section: Discussionmentioning

confidence: 99%

MicroRNA miR-155 Is Necessary for Efficient Gammaherpesvirus Reactivation from Latency, but Not for Establishment of Latency

Crepeau

Zhang

Usherwood

2016

J Virol

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MicroRNA-155 (miR-155) has been shown to play significant roles in the immune response, including in the formation of germinal centers (GC) and the development and maturation of T follicular helper (Tfh) cells. There is in vitro evidence to support a critical role for cellular miR-155 and viral miR-155 homologs in the establishment of gammaherpesvirus latency in B cells. We sought to determine the contribution of miR-155 to the establishment and maintenance of latency in vivo using murine gammaherpesvirus (MHV-68) infection. MHV-68-infected mice deficient in miR-155 exhibited decreases in GC B cells and Tfh cells. However, the frequencies of spleen cells harboring latent MHV-68 genomes were the same in both miR-155-deficient and wildtype (WT) mice. Similar latent loads were also observed in mixed bone marrow chimeric mice, where B cell-extrinsic effects of miR-155 deficiency were normalized. Interestingly, we observed markedly lower efficiency of reactivation from latency in miR-155-deficient cells, indicating an important role for miR-155 in this process. These in vivo data complement previous in vitro studies and lead to the conclusion that miR-155 is not necessary for the establishment or maintenance of gammaherpesvirus latency but that it does affect reactivation efficiency. IMPORTANCEGammaherpesvirus infection leads to severe disease in immunosuppressed populations. miR-155 has been shown to play important roles in many pathological processes, including tumorigenesis and diseases caused by an overly aggressive immune response. Our work provides valuable in vivo data showing that miR-155 is dispensable for gammaherpesvirus latency but that it is critical for reactivation from latency, which is a crucial step in the viral life cycle. The herpesvirus family is a large and widely distributed family of double-stranded, enveloped DNA viruses. Their anatomical sites of latency and frequency of reactivation vary, resulting in a range of clinical manifestations. A defining feature of this virus family is the ability to establish latent infection within host cells. The gammaherpesviruses distinguish themselves by being lymphotropic, in most cases establishing latency in B cells, where coordinated programs of viral and host gene expression promote B cell differentiation to favor virus latency.Gammaherpesviruses are of clinical interest due to the two human members of this viral subfamily: Epstein-Barr virus (EBV; human herpesvirus 4 [HHV-4]) and Kaposi's sarcoma-associated herpesvirus (KSHV; HHV-8). These viruses are closely associated with the development of malignancies in immunosuppressed populations. EBV was initially recovered from an endemic form of Burkitt's lymphoma, and it has been shown to hijack the B cell differentiation pathway in order to gain access into the long-lived memory B cell compartment (1). Due to the narrow host tropism and seroprevalence of the human gammaherpesviruses, murine gammaherpesvirus (MHV-68) has become a critical model system in which to examine the in vivo immunobiology of...

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KSHV miRNAs Decrease Expression of Lytic Genes in Latently Infected PEL and Endothelial Cells by Targeting Host Transcription Factors

Cited by 39 publications

References 65 publications

A KSHV microRNA enhances viral latency and induces angiogenesis by targeting GRK2 to activate the CXCR2/AKT pathway

A KSHV microRNA enhances viral latency and induces angiogenesis by targeting GRK2 to activate the CXCR2/AKT pathway

Small RNAs growing tall: miRNAs as drug targets in herpesvirus infections

MicroRNA miR-155 Is Necessary for Efficient Gammaherpesvirus Reactivation from Latency, but Not for Establishment of Latency

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