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Molecular and Cellular Biology, September 2003, p. 6618-6630, Vol. 23, No. 18
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.18.6618-6630.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

PSF Acts through the Human Immunodeficiency Virus Type 1 mRNA Instability Elements To Regulate Virus Expression

Andrei S. Zolotukhin,1 Daniel Michalowski,1 Jenifer Bear,1 Sergey V. Smulevitch,1 Abdulmaged M. Traish,2 Rui Peng,3 James Patton,3 Ivan N. Shatsky,4 and Barbara K. Felber1*

Human Retrovirus Pathogenesis Section, Basic Research Laboratory, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland 21702-1201,1 Department of Biochemistry, School of Medicine, Boston University, Boston, Massachusetts 02118,2 Department of Molecular Biology, Vanderbilt University, Nashville, Tennessee 37235-1820,3 A. N. Belozersky Institute, Moscow State University, Moscow, Russia4

Received 7 May 2003/ Returned for modification 30 May 2003/ Accepted 11 June 2003

Human immunodeficiency virus type 1 (HIV) gag/pol and env mRNAs contain cis-acting regulatory elements (INS) that impair stability, nucleocytoplasmic transport, and translation by unknown mechanisms. This downregulation can be counteracted by the viral Rev protein, resulting in efficient export and expression of these mRNAs. Here, we show that the INS region in HIV-1 gag mRNA is a high-affinity ligand of p54nrb/PSF, a heterodimeric transcription/splicing factor. Both subunits bound INS RNA in vitro with similar affinity and specificity. Using an INS-containing subgenomic gag mRNA, we show that it specifically associated with p54nrb in vivo and that PSF inhibited its expression, acting via INS. Studying the authentic HIV-1 mRNAs produced from an infectious molecular clone, we found that PSF affected specifically the INS-containing, Rev-dependent transcripts encoding Gag-Pol and Env. Both subunits contained nuclear export and nuclear retention signals, whereas p54nrb was continuously exported from the nucleus and associated with INS-containing mRNA in the cytoplasm, suggesting its additional role at late steps of mRNA metabolism. Thus, p54nrb and PSF have properties of key factors mediating INS function and likely define a novel mRNA regulatory pathway that is hijacked by HIV-1.

* Corresponding author. Mailing address: NCI-Frederick, Bldg. 535, Rm. 110, Frederick, MD 21702-1201. Phone: (301) 846-5159. Fax: (301) 846-7146. E-mail: felber{at}mail.ncifcrf.gov.

Molecular and Cellular Biology, September 2003, p. 6618-6630, Vol. 23, No. 18
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.18.6618-6630.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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