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J. Biol. Chem., Vol. 281, Issue 48, 37150-37158, December 1, 2006

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Human T-cell Leukemia Virus Type I p30 Nuclear/Nucleolar Retention Is Mediated through Interactions with RNA and a Constituent of the 60 S Ribosomal Subunit^*

Sofiane Ghorbel, Uma Sinha-Datta, Miroslav Dundr^¶, Megan Brown, Genoveffa Franchini, and Christophe Nicot¹

From the Department of Microbiology, Molecular Genetics, and Immunology, University of Kansas Medical Center, Kansas City, Kansas 66160-7420, the Animal Models and Retroviral Vaccines Section, NCI, National Institutes of Health, Bethesda, Maryland 20892-5065, and the ^¶Department of Cell Biology and Anatomy, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois 60064

Human T-cell leukemia virus type I is the etiological agent of adult T-cell leukemia/lymphoma, an aggressive and fatal lymphoproliferative malignancy. The virus has evolved strategies to escape immune clearance by remaining latent in most infected cells in vivo. We demonstrated previously that virally encoded p30 protein is a potent post-transcriptional inhibitor of virus replication (Nicot, C., Dundr, M., Johnson, J. M., Fullen, J. R., Alonzo, N., Fukumoto, R., Princler, G. L., Derse, D., Misteli, T., and Franchini, G. (2004) Nat. Med. 10, 197-201). p30 is unable to shuttle out of the nucleus in heterokaryon assays, suggesting the existence of specific retention signals. Because suppression of virus replication relies on nuclear retention of the tax/rex mRNA by p30, determining the retention features of p30 will offer hints to break latency in infected cells and insights into new therapeutic approaches. In this study, we used live cell imaging technologies to study the kinetics of p30 and to delineate its retention signals and their function in virus replication. Notably, this is the first study to identify p30 nucleolar retention domains. Using mutants of p30 that localized in different cellular compartments, we show that post-transcriptional control of virus replication by p30 occurs in the nucleoplasm. We further demonstrate that p30 nuclear/nucleolar retention is dependent upon de novo RNA transcripts and interactions with components of the ribosomal machinery.

Received for publication, April 26, 2006 , and in revised form, September 7, 2006.

^* This work was supported by NIAID Grant AI058944 from the National Institutes of Health (to C. N.) and by Centers of Biomedical Research Excellence Program Grant P20 RR016443 from the National Center for Research Resources, National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Microbiology, Immunology, and Molecular Genetics, University of Kansas Medical Center, 3025 Wahl Hall West, 3901 Rainbow Blvd., Kansas City, KS 66160-7420. Tel.: 913-588-6724; Fax: 913-588-7295; E-mail: cnicot{at}kumc.edu.

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