PRMT5 Is Upregulated in HTLV-1-Mediated T-Cell Transformation and Selective Inhibition Alters Viral Gene Expression and Infected Cell Survival

Viruses

Amanda R. Panfil³  Jacob Al-Saleem³  Cory M. Howard³  Jessica M. Mates¹  Jesse J. Kwiek³  Robert A. Baiocchi²  Patrick L. Green³ 

[1] Center for Microbial Interface Biology, The Ohio State University, Columbus, OH 43210, USA;Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA;Center for Retrovirus Research, The Ohio State University, Columbus, OH 43210, USA;

关键词: HTLV-1;    PRMT5;    transformation;    ATLL;    Tax;    HBZ;    p30;    lymphoma;   

DOI  :  10.3390/v8010007

来源: mdpi

【 摘 要 】

Human T-cell leukemia virus type-1 (HTLV-1) is a tumorigenic retrovirus responsible for development of adult T-cell leukemia/lymphoma (ATLL). This disease manifests after a long clinical latency period of up to 2–3 decades. Two viral gene products, Tax and HBZ, have transforming properties and play a role in the pathogenic process. Genetic and epigenetic cellular changes also occur in HTLV-1-infected cells, which contribute to transformation and disease development. However, the role of cellular factors in transformation is not completely understood. Herein, we examined the role of protein arginine methyltransferase 5 (PRMT5) on HTLV-1-mediated cellular transformation and viral gene expression. We found PRMT5 expression was upregulated during HTLV-1-mediated T-cell transformation, as well as in established lymphocytic leukemia/lymphoma cell lines and ATLL patient PBMCs. shRNA-mediated reduction in PRMT5 protein levels or its inhibition by a small molecule inhibitor (PRMT5i) in HTLV-1-infected lymphocytes resulted in increased viral gene expression and decreased cellular proliferation. PRMT5i also had selective toxicity in HTLV-1-transformed T-cells. Finally, we demonstrated that PRMT5 and the HTLV-1 p30 protein had an additive inhibitory effect on HTLV-1 gene expression. Our study provides evidence for PRMT5 as a host cell factor important in HTLV-1-mediated T-cell transformation, and a potential target for ATLL treatment.

【 授权许可】

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