This Article Full Text Full Text (PDF) Supplemental material Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Corcoran, J. A. Articles by Smiley, J. R. Search for Related Content PubMed PubMed Citation Articles by Corcoran, J. A. Articles by Smiley, J. R.

 Previous Article  |  Next Article 

Journal of Virology, March 2009, p. 2601-2610, Vol. 83, No. 6
0022-538X/09/$08.00+0     doi:10.1128/JVI.02087-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Herpes Simplex Virus UL12.5 Targets Mitochondria through a Mitochondrial Localization Sequence Proximal to the N Terminus ^,

Jennifer A. Corcoran, Holly A. Saffran, Brett A. Duguay, and James R. Smiley^*

Alberta Institute for Viral Immunology, Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta T6G 2S2, Canada

Received 3 October 2008/ Accepted 29 December 2008

The herpes simplex virus type 1 (HSV-1) gene UL12 encodes a conserved alkaline DNase with orthologues in all herpesviruses. The HSV-1 UL12 gene gives rise to two separately promoted 3' coterminal mRNAs which encode distinct but related proteins: full-length UL12 and UL12.5, an amino-terminally truncated form that initiates at UL12 codon 127. Full-length UL12 localizes to the nucleus where it promotes the generation of mature viral genomes from larger precursors. In contrast, UL12.5 is predominantly mitochondrial and acts to trigger degradation of the mitochondrial genome early during infection. We examined the basis for these very different subcellular localization patterns. We confirmed an earlier report that the amino-terminal region of full-length UL12 is required for nuclear localization and provide evidence that multiple nuclear localization determinants are present in this region. In addition, we demonstrate that mitochondrial localization of UL12.5 relies largely on sequences located between UL12 residues 185 and 245 (UL12.5 residues 59 to 119). This region contains a sequence that resembles a typical mitochondrial matrix localization signal, and mutations that reduce the positive charge of this element severely impaired mitochondrial localization. Consistent with matrix localization, UL12.5 displayed a detergent extraction profile indistinguishable from that of the matrix protein cyclophilin D. Mitochondrial DNA depletion required the exonuclease activity of UL12.5, consistent with the idea that UL12.5 located within the matrix acts directly to destroy the mitochondrial genome. These results clarify how two highly related viral proteins are targeted to different subcellular locations with distinct functional consequences.

---

* Corresponding author. Mailing address: Alberta Institute for Viral Immunology, Department of Medical Microbiology and Immunology, 632 Heritage Medical Research Center, University of Alberta, Edmonton, Alberta T6G 2S2, Canada. Phone: (780) 492-4070. Fax: (780) 492-9828. E-mail: jim.smiley{at}ualberta.ca

Published ahead of print on 7 January 2009.

Supplemental material for this article may be found at http://jvi.asm.org/.

Present address: Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada B3H 1X5.

---

Journal of Virology, March 2009, p. 2601-2610, Vol. 83, No. 6
0022-538X/09/$08.00+0     doi:10.1128/JVI.02087-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.