Cytomegalovirus cell death suppressor vMIA blocks Bax- but not Bak-mediated apoptosis by binding and sequestering Bax at mitochondria

Abstract

We report that the cytomegalovirus-encoded cell death suppressor vMIA binds Bax and prevents Bax-mediated mitochondrial membrane permeabilization by sequestering Bax at mitochondria in the form of a vMIA–Bax complex. vMIA mutants with a defective mitochondria-targeting domain retain their Bax-binding function but not their ability to suppress mitochondrial membrane permeabilization or cell death. vMIA does not seem to either specifically associate with Bak or suppress Bak-mediated mitochondrial membrane permeabilization. Recent evidence suggests that the contribution of Bax and Bak in the mitochondrial apoptotic signaling pathway depends on the distinct phenotypes of cells, and it appears from our data that vMIA is capable of suppressing apoptosis in cells in which this pathway is dominated by Bax, but not in cells where Bak also plays a role.

Mitochondrial and Secretory Human Cytomegalovirus UL37 Proteins Traffic into Mitochondrion-Associated Membranes of Human Cells

“…When the bridges transiently form between the MAM and mitochondria, UL37 proteins could traffic into the mitochondrial outer membrane, where they have antiapoptotic activity. Its topology and anchoring to membranes enables pUL37x1 to preferentially interact with the membrane-bound proapoptotic Bax protein, inducing its oligomerization and leading to its functional neutralization (5,32). Nonetheless, the finding that multiple HCMV UL37 proteins traffic into the MAM, whereas only a subset of these is specifically committed into mitochondrial importation, shows that MAM localization is insufficient to commit UL37 proteins into mitochondrial importation.…”

“…These sequences include a strongly hydrophobic leader (aa 1 to 22) and a juxtaposed basic domain (aa 23 to 34), which jointly serve as a bipartite signal to target UL37 proteins to the ER and mitochondria (25,27). This NH 2 -terminal targeting domain constitutes the first UL37x1 antiapoptotic domain, which when combined with a downstream domain (aa 118 to 147) are sufficient to confer its antiapoptotic activity (5,18,19,28,32,34,45). Between the UL37x1 antiapoptotic domains lies an acidic domain (aa 81 to 108), which plays a role in the transactivation of HCMV early gene promoters, whose products are needed for its oriLyt replication (13,31,52).…”

Modified vaccinia virus Ankara protein F1L is a novel BH3-domain-binding protein and acts together with the early viral protein E3L to block virus-associated apoptosis

“…However, the antiapoptotic proteins expressed by human cytomegalovirus vMIA and that expressed by myxoma virus M11L sequester Bax 31 and Bak, 32 respectively. To test this hypothesis for F1L-function, we initially assessed the capacity of purified recombinant F1L expressed in Escherichia coli to bind Bcl-2 homology domain (BH3 domain) peptides since these regions mediate the killing activity of the proapoptotic BH3-only proteins as well as Bax/Bak.…”

Caught in the act – protein adaptation and the expanding roles of the PACS proteins in tissue homeostasis and disease

“…Conversely, PACS-1 can bind de-phosphorylated Bid and block translocation to mitochondria, suggesting a mechanism to impede the apoptotic program. In HCMV-infected cells, vMIA traps PACS-2 and Bax on mitochondria, suppressing Bid recruitment and MOMP (Arnoult et al, 2004;Salka et al, 2017; Fig. 5A,C).…”

“…Not surprisingly, herpesviruses also exploit the ability of PACS-2 to traffic proteins to mitochondria. The HCMV protein viral inhibitor of apoptosis (vMIA) prevents cell death by trapping proapoptotic Bax on mitochondria (Arnoult et al, 2004). vMIA interacts with PACS-2 but not PACS-1 (our unpublished data), and the vMIA- PACS-2 interaction is required for efficient translocation of vMIA to mitochondria (Salka et al, 2017).…”