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Regulation of NF-κB inhibitor IκBα and viral replication by a KSHV microRNA

Nature Cell Biology volume 12, pages 193–199 (2010)Cite this article

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A Corrigendum to this article was published on 01 June 2010

Abstract

Kaposi's sarcoma-associated herpesvirus (KSHV) is causally linked to several acquired immune deficiency syndrome-related malignancies, including Kaposi's sarcoma, primary effusion lymphoma (PEL) and a subset of multicentric Castleman's disease1. Control of viral lytic replication is essential for KSHV latency, evasion of the host immune system and induction of tumours1. Here, we show that deletion of a 14 microRNA (miRNA) cluster from the KSHV genome significantly enhances viral lytic replication as a result of reduced NF-κB activity. The miRNA cluster regulates the NF-κB pathway by reducing expression of IκBα protein, an inhibitor of NF-κB complexes. Computational and miRNA seed mutagenesis analyses were used to identify KSHV miR-K1, which directly regulates the IκBα protein level by targeting the 3′UTR of its transcript. Expression of miR-K1 is sufficient to rescue NF-κB activity and inhibit viral lytic replication, whereas inhibition of miR-K1 in KSHV-infected PEL cells has the opposite effect. Thus, KSHV encodes an miRNA to control viral replication by activating the NF-κB pathway. These results demonstrate an important role for KSHV miRNAs in regulating viral latency and lytic replication by manipulating the host survival pathway.

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Figure 1: KSHV miRNA cluster inhibits viral lytic replication.
Figure 2: A KSHV miRNA cluster enhances NF-κB activity to inhibit viral lytic replication.
Figure 3: A KSHV miRNA cluster regulates the NF-κB pathway through direct targeting of the IκBα 3′UTR by miR-K1.
Figure 4: KSHV miR-K1 inhibits viral lytic replication by enhancing NF-κB activity.

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Acknowledgements

We thank K. Izumi and A. Griffiths for their valuable suggestions. This work was supported by grants from the American Cancer Society (#RSG-04-195) and the National Institutes of Health (CA096512, CA124332, CA132637 and DE017333) to S.-J.G, and the National Science Foundation (CCF-0546345) to Y.F.H. C.-G.K. was supported by Konkuk University in 2008.

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Author notes

  1. Xiufen Lei and Zhiqiang Bai: These authors contributed equally to this work.

Authors and Affiliations

  1. Tumor Virology Program, Greehey Children's Cancer Research Institute, and Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, San Antonio, 78229, TX, USA

    Xiufen Lei, Zhiqiang Bai, Fengchun Ye, Jianping Xie, Chan-Gil Kim, Yufei Huang & Shou-Jiang Gao

  2. Department of Pediatrics, Microbiology and Immunology, Medicine, and Molecular Medicine, and Cancer Therapy and Research Center, The University of Texas Health Science Center at San Antonio, San Antonio, 78229, TX, USA

    Xiufen Lei, Zhiqiang Bai, Fengchun Ye, Jianping Xie & Shou-Jiang Gao

  3. Tumor Virology Group, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, 430071, Hubei, China

    Zhiqiang Bai & Shou-Jiang Gao

  4. Graduate University of the Chinese Academy of Sciences, Beijing, 100039, China

    Zhiqiang Bai & Shou-Jiang Gao

  5. Department of Biotechnology, Konkuk University, Chungju, 380-701, Korea

    Chan-Gil Kim

  6. Department of Electrical and Computer Engineering, The University of Texas at San Antonio, San Antonio, 78249, TX, USA

    Yufei Huang

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Contributions

X.F.L. performed genetic, viral replication, NF-κB-related analysis and mRNA suppressor experiments (Figs 1, 2, 3, 4; Supplementary Information, Figs S1–S3, S5, S6 and S8); Z.Q.B. performed bioinformatics, mutagenesis of the miRNA target and part of the genetics and viral replication (Figs 2 and 3; Supplementary Information, Figs S1, S4, S7 and S8); X.P.X. conducted EMSA (Fig. 2); F.C.Y. contributed to viral genetics and northern blotting (Fig. 4; Supplementary Information, Fig. S1); C.G.K. contributed to target identification (Supplementary Information, Fig. S7); Y.F.H. contributed to bioinformatics (Fig. 3); S.J.G. directed, designed and analysed all the experiments and data; X.F.L. and S.J.G. wrote the manuscript.

Corresponding author

Correspondence to Shou-Jiang Gao.

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Lei, X., Bai, Z., Ye, F. et al. Regulation of NF-κB inhibitor IκBα and viral replication by a KSHV microRNA. Nat Cell Biol 12, 193–199 (2010). https://doi.org/10.1038/ncb2019

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