MCMV-mediated Inhibition of the Pro-apoptotic Bak Protein Is Required for Optimal In Vivo Replication
- Author(s)
- Fleming, P; Kvansakul, M; Voigt, V; Kile, BT; Kluck, RM; Huang, DCS; Degli-Esposti, MA; Andoniou, CE;
- Details
- Publication Year 2013-02,Volume 9,Issue #2,Page e1003192
- Journal Title
- PLOS PATHOGENS
- Publication Type
- Journal Article
- Abstract
- Successful replication and transmission of large DNA viruses such as the cytomegaloviruses (CMV) family of viruses depends on the ability to interfere with multiple aspects of the host immune response. Apoptosis functions as a host innate defence mechanism against viral infection, and the capacity to interfere with this process is essential for the replication of many viruses. The Bcl-2 family of proteins are the principle regulators of apoptosis, with two pro-apoptotic members, Bax and Bak, essential for apoptosis to proceed. The m38.5 protein encoded by murine CMV (MCMV) has been identified as Bax-specific inhibitor of apoptosis. Recently, m41.1, a protein product encoded by the m41 open reading frame (ORF) of MCMV, has been shown to inhibit Bak activity in vitro. Here we show that m41.1 is critical for optimal MCMV replication in vivo. Growth of a m41.1 mutant was attenuated in multiple organs, a defect that was not apparent in Bak(-/-) mice. Thus, m41.1 promotes MCMV replication by inhibiting Bak-dependent apoptosis during in vivo infection. The results show that Bax and Bak mediate non-redundant functions during MCMV infection and that the virus produces distinct inhibitors for each protein to counter the activity of these proteins.
- Publisher
- PUBLIC LIBRARY SCIENCE
- Keywords
- MURINE CYTOMEGALOVIRUS-INFECTION; CELL-DEATH; MITOCHONDRIAL MORPHOGENESIS; MEMBRANE PERMEABILIZATION; DENDRITIC CELLS; BCL-2; DISSEMINATION; PATHWAY; FAMILY; MACROPHAGES
- Research Division(s)
- Cancer And Haematology; Molecular Genetics Of Cancer; Chemical Biology
- Publisher's Version
- https://doi.org/10.1371/journal.ppat.1003192
- Open Access at Publisher's Site
http://www.plospathogens.org/article/info%3Adoi%2F10.1371%2Fjournal.ppat.1003192- Terms of Use/Rights Notice
- Copyright: © 2013 Fleming et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Creation Date: 2013-02-01 12:00:00