title: Human cytomegalovirus inhibits apoptosis by proteasome-mediated degradation of Bax at endoplasmic reticulum-mitochondrion contacts.
abstract: Human cytomegalovirus (HCMV) encodes the UL37 exon 1 protein (pUL37x1), which is the potent viral mitochondrion-localized inhibitor of apoptosis (vMIA), to increase survival of infected cells. HCMV vMIA traffics from the endoplasmic reticulum (ER) to ER subdomains, which are physically linked to mitochondria known as mitochondrion-associated membranes (MAM), and to mitochondria. The antiapoptotic function of vMIA is thought to primarily result from its ability to inhibit Bax-mediated permeabilization of the outer mitochondrial membrane (OMM). Here, we establish that vMIA retargets Bax to the MAM as well as to the OMM from immediate early through late times of infection. However, MAM localization of Bax results in its increased ubiquitination and proteasome-mediated degradation. Surprisingly, HCMV infection does not increase OMM-associated degradation (OMMAD) of Bax, even though the ER and mitochondria are physically connected at the MAM. It was recently found that lipid rafts at the plasma membrane can connect extrinsic and intrinsic apoptotic pathways and can serve as sites of apoptosome assembly. In transfected permissive human fibroblasts, vMIA mediates, through its cholesterol affinity, association of Bax and apoptosome components with MAM lipid rafts. While Bax association with MAM lipid rafts was detected in HCMV-infected cells, association of apoptosome components was not. These results establish that Bax recruitment to the MAM and its MAM-associated degradation (MAMAD) are a newly described antiapoptotic mechanism used by HCMV infection to increase cell survival for its growth.
authors.affiliation: Research Center for Genetic Medicine, Children's Research Institute, Children's National Medical Center, Washington, DC, USA.
authors.forename: Aiping
authors.initials: A
authors.lastname: Zhang
authors.forename: Richard L
authors.initials: RL
authors.lastname: Hildreth
authors.forename: Anamaris M
authors.initials: AM
authors.lastname: Colberg-Poley
mesh_terms: D017209:Apoptosis; D002460:Cell Line; D003587:Cytomegalovirus / Q000472:pathogenicity*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005347:Fibroblasts / Q000821:virology; D054884:Host-Pathogen Interactions; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D059748:Proteolysis; D051028:bcl-2-Associated X Protein / Q000037:antagonists & inhibitors*
chemical_list: C494826:BAX protein, human; D017874:Immediate-Early Proteins; C420323:UL37 protein, Human herpesvirus 5; D051028:bcl-2-Associated X Protein; D046988:Proteasome Endopeptidase Complex