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Journal of Virology, December 2005, p. 14737-14747, Vol. 79, No. 23
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.23.14737-14747.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Mouse Mammary Tumor Virus Encodes a Self-Regulatory RNA Export Protein and Is a Complex Retrovirus

Jennifer A. Mertz,{dagger} Melissa S. Simper,{dagger},{ddagger} Mary M. Lozano, Shelley M. Payne, and Jaquelin P. Dudley*

Section of Molecular Genetics and Microbiology and Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas 78712

Received 28 July 2005/ Accepted 12 September 2005

Mouse mammary tumor virus (MMTV) has been classified as a simple retrovirus with two accessory genes, dut and sag. Cloned MMTV proviruses carrying a trimethoprim (trim) cassette in the envelope gene were defective for Gag protein production and the nuclear export of unspliced gag-pol RNA. Complementation experiments indicated that a trans-acting product was responsible for the Gag defect of such mutants. Analysis of MMTV-infected cells revealed the presence of a novel, doubly spliced RNA that encodes a putative product of 301 amino acids. Overexpression of cDNA from this RNA increased Gag levels from env mutant proviruses or reporter gene expression from unspliced mRNAs and allowed detection of a 33-kDa protein product, which has been named regulator of export of MMTV mRNA, or Rem. The Rem N terminus has motifs similar to the Rev-like export proteins of complex retroviruses, and mutation of the nuclear localization signal (NLS) abolished RNA export and detection within the nucleus. The Rem C terminus has few identifiable features, but removal of this domain increased Rem-mediated export, suggesting an autoregulatory function. A reporter vector developed from the 3' end of the MMTV provirus was Rem responsive and required both the presence of the MMTV env-U3 junction and a functional Crm1 pathway. The identification of a third accessory protein from a doubly spliced transcript suggests that MMTV is the first murine complex retrovirus to be documented. Manipulation of the MMTV genome may provide mouse models for human retroviral diseases, such as AIDS.

* Corresponding author. Mailing address: The University of Texas at Austin, Section of Molecular Genetics and Microbiology, One University Station, A5000, Austin, TX 78712-0162. Phone: (512) 471-8415. Fax: (512) 471-7088. E-mail: jdudley{at}uts.cc.utexas.edu.

{dagger} J.A.M. and M.S.S. contributed equally to this work.

{ddagger} Present address: University of Texas M.D. Anderson Cancer Center at Science Park, Smithville, TX 78957.

Journal of Virology, December 2005, p. 14737-14747, Vol. 79, No. 23
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.23.14737-14747.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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