Immunology and Virology Program, Centre for Ophthalmology and Visual Science, The University of Western Australia, Nedlands, Western Australia, Australia.
PLoS Pathog. 2013 Feb;9(2):e1003192. doi: 10.1371/journal.ppat.1003192. Epub 2013 Feb 28.
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.
成功复制和传播巨细胞病毒（CMV）家族等大型 DNA 病毒依赖于干扰宿主免疫反应多个方面的能力。细胞凋亡是宿主抵抗病毒感染的固有防御机制，而干扰这一过程的能力对于许多病毒的复制至关重要。Bcl-2 蛋白家族是细胞凋亡的主要调节因子，两个促凋亡成员 Bax 和 Bak 对于凋亡的进行是必不可少的。鼠巨细胞病毒（MCMV）编码的 m38.5 蛋白被鉴定为 Bax 特异性凋亡抑制剂。最近，MCMV m41 开放阅读框（ORF）编码的蛋白产物 m41.1 已被证明可在体外抑制 Bak 活性。在这里，我们表明 m41.1 对于体内 MCMV 的最佳复制至关重要。m41.1 突变体在多个器官中的生长受到抑制，而在 Bak(-/-) 小鼠中则没有明显的缺陷。因此，m41.1 通过抑制 Bak 依赖性凋亡促进体内感染期间的 MCMV 复制。结果表明，Bax 和 Bak 在 MCMV 感染过程中介导非冗余功能，并且病毒产生针对每种蛋白的独特抑制剂来对抗这些蛋白的活性。
