scholarly journals CircRNA ARFGEF1 functions as a ceRNA to promote oncogenic KSHV-encoded viral interferon regulatory factor induction of cell invasion and angiogenesis by upregulating glutaredoxin 3

2021 ◽  
Vol 17 (2) ◽  
pp. e1009294
Author(s):  
Shuihong Yao ◽  
Xuemei Jia ◽  
Fei Wang ◽  
Liuxue Sheng ◽  
Pengxia Song ◽  
...  

Circular RNAs (circRNAs) are novel single-stranded noncoding RNAs that can decoy other RNAs to inhibit their functions. Kaposi’s sarcoma (KS), caused by oncogenic Kaposi’s sarcoma-associated herpesvirus (KSHV), is a highly angiogenic and invasive vascular tumor of endothelial origin commonly found in AIDS patients. We have recently shown that KSHV-encoded viral interferon regulatory factor 1 (vIRF1) induces cell invasion, angiogenesis and cellular transformation; however, the role of circRNAs is largely unknown in the context of KSHV vIRF1. Herein, transcriptome analysis identified 22 differentially expressed cellular circRNAs regulated by vIRF1 in an endothelial cell line. Among them, circARFGEF1 was the highest upregulated circRNA. Mechanistically, vIRF1 induced circARFGEF1 transcription by binding to transcription factor lymphoid enhancer binding factor 1 (Lef1). Importantly, upregulation of circARFGEF1 was required for vIRF1-induced cell motility, proliferation and in vivo angiogenesis. circARFGEF1 functioned as a competing endogenous RNAs (ceRNAs) by binding to and inducing degradation of miR-125a-3p. Mass spectrometry analysis demonstrated that glutaredoxin 3 (GLRX3) was a direct target of miR-125a-3p. Knockdown of GLRX3 impaired cell motility, proliferation and angiogenesis induced by vIRF1. Taken together, vIRF1 transcriptionally activates circARFGEF1, potentially by binding to Lef1, to promote cell oncogenic phenotypes via inhibiting miR-125a-3p and inducing GLRX3. These findings define a novel mechanism responsible for vIRF1-induced oncogenesis and establish the scientific basis for targeting these molecules for treating KSHV-associated cancers.

2001 ◽  
Vol 75 (13) ◽  
pp. 6193-6198 ◽  
Author(s):  
Taegun Seo ◽  
Junsoo Park ◽  
Daeyoup Lee ◽  
Sun Gwan Hwang ◽  
Joonho Choe

ABSTRACT Kaposi's sarcoma-associated herpesvirus (KSHV) is related to the development of Kaposi's sarcoma. Open reading frame K9 of KSHV encodes viral interferon regulatory factor 1 (vIRF1), which functions as a repressor of interferon- and IRF1-mediated signal transduction. In addition, vIRF1 acts as an oncogene to induce cellular transformation. Here we show that vIRF1 directly associates with the tumor suppressor p53 and represses its functions. The vIRF1 interaction domains of p53 are the DNA binding domain (amino acids [aa] 100 to 300) and the tetramerization domain (aa 300 to 393). p53 interacts with the central region (aa 152 to 360) of vIRF1. vIRF1 suppresses p53-dependent transcription and deregulates its apoptotic activity. These results suggest that vIRF1 may regulate cellular function by inhibiting p53.


2010 ◽  
Vol 84 (23) ◽  
pp. 12255-12264 ◽  
Author(s):  
Katharina Heinzelmann ◽  
Barbara A. Scholz ◽  
Agnes Nowak ◽  
Even Fossum ◽  
Elisabeth Kremmer ◽  
...  

ABSTRACT In cells infected with the Kaposi's sarcoma-associated herpesvirus (KSHV), CSL/CBF1 signaling is essential for viral replication and promotes the survival of KSHV-infected cells. CSL/CBF1 is a DNA adaptor molecule which recruits coactivator and corepressor complexes to regulate viral and cellular gene transcription and which is a major downstream effector molecule of activated Notch. The interaction of KSHV RTA and LANA with CSL/CBF1 has been shown to balance the lytic and latent viral life cycle. Here we report that a third KSHV protein, viral interferon regulatory factor 4 (vIRF4/K10), but none of the three other KSHV-encoded vIRFs, interacts with CSL/CBF1. Two regions of vIRF4 with dissimilar affinities contribute to CSL/CBF1 binding. Similar to Notch, vIRF4 targets the hydrophobic pocket in the beta trefoil domain of CSL/CBF1 through a short peptide motif which closely resembles a motif found in Notch but does not strictly follow the ΦWΦP consensus conserved in human and mouse Notch proteins. Our results suggest that vIRF4 might compete with Notch for CSL/CBF1 binding and signaling.


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