Jurak I, Schumacher U, Simic H, Voigt S, Brune W (2008): The murine cytomegalovirus m38.5 protein inhibits Bax-mediated cell death
J. Virol. 82 (10): 4812-4822. Epub Mar 5.

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 apoptosis of murine cells, and its role during MCMV infection have not been investigated. Here we show that m38.5 is expressed at early times during MCMV infection. Cells infected with MCMVs lacking m38.5 showed increased sensitivity to cell death induced by staurosporine (STS), MG132, or the viral infection itself. This defect was rescued when m38.5 or bcl-X_L was inserted into the genome of a deletion mutant. Using fibroblasts deficient for the proapoptotic Bcl-2 family proteins Bak and/or Bax we further demonstrate that m38.5 protects from Bax- but not Bak-mediated apoptosis and interacts with Bax in infected cells. These results consolidate the role of m38.5 as a viral mitochondria-localized inhibitor of apoptosis (vMIA) and its functional similarity to the human cytomegalovirus UL37x1 gene product. Although m38.5 is not homologous to UL37x1 on the sequence level, it is conserved among rodent CMVs. 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.