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Journal of Virology, May 2008, p. 4812-4822, Vol. 82, No. 10
0022-538X/08/$08.00+0     doi:10.1128/JVI.02570-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Murine Cytomegalovirus m38.5 Protein Inhibits Bax-Mediated Cell Death{triangledown}

Igor Jurak ,1,{dagger},{ddagger} Uwe Schumacher,1,{ddagger} Hrvoje Simic,2 Sebastian Voigt,1 and Wolfram Brune1*

Division of Viral Infections, Robert Koch Institute, 13353 Berlin, Germany,1 Department of Histology and Embryology, Medical Faculty, University of Rijeka, 51000 Rijeka, Croatia2

Received 3 December 2007/ Accepted 27 February 2008

Many viruses encode proteins that inhibit the induction of programmed cell death at the mitochondrial checkpoint. Murine cytomegalovirus (MCMV) encodes the m38.5 protein, which localizes to mitochondria and protects human HeLa cells and fibroblasts from apoptosis triggered by proteasome inhibitors but not from Fas-induced apoptosis. However, the ability of this protein to suppress the apoptosis of murine cells and its role during MCMV infection have not been investigated previously. Here we show that m38.5 is expressed at early time points during MCMV infection. Cells infected with MCMVs lacking m38.5 showed increased sensitivity to cell death induced by staurosporine, MG132, or the viral infection itself compared to the sensitivity of cells infected with wild-type MCMV. This defect was eliminated when an m38.5 or Bcl-XL gene was inserted into the genome of a deletion mutant. Using fibroblasts deficient in the proapoptotic Bcl-2 family proteins Bak and/or Bax, we further demonstrated that m38.5 protected from Bax- but not Bak-mediated apoptosis and interacted with Bax in infected cells. These results consolidate the role of m38.5 as a viral mitochondrion-localized inhibitor of apoptosis and its functional similarity to the human cytomegalovirus UL37x1 gene product. Although the m38.5 gene is not homologous to the UL37x1 gene at the sequence level, m38.5 is conserved among rodent cytomegaloviruses. Moreover, the fact that MCMV-infected cells are protected from both Bak- and Bax-mediated cell death suggests that MCMV possesses an additional, as-yet-unidentified mechanism to block Bak-mediated apoptosis.

* Corresponding author. Mailing address: Division of Viral Infections, Robert Koch Institute, Nordufer 20, 13353 Berlin, Germany. Phone: 49 30 18754 2502. Fax: 49 30 1810754 2502. E-mail: BruneW{at}rki.de

{triangledown} Published ahead of print on 5 March 2008.

{dagger} Present address: Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115.

{ddagger} I.J. and U.S. contributed equally to this work.

Journal of Virology, May 2008, p. 4812-4822, Vol. 82, No. 10
0022-538X/08/$08.00+0     doi:10.1128/JVI.02570-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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