A cytomegalovirus-encoded mitochondria-localized inhibitor of apoptosis structurally unrelated to Bcl-2

Abstract

Human cytomegalovirus (CMV), a herpesvirus that causes congenital disease and opportunistic infections in immunocompromised individuals, encodes functions that facilitate efficient viral propagation by altering host cell behavior. Here we show that CMV blocks apoptosis mediated by death receptors and encodes a mitochondria-localized inhibitor of apoptosis, denoted vMIA, capable of suppressing apoptosis induced by diverse stimuli. vMIA, a product of the viral UL37 gene, inhibits Fas-mediated apoptosis at a point downstream of caspase-8 activation and Bid cleavage but upstream of cytochrome c release, while residing in mitochondria and associating with adenine nucleotide translocator. These functional properties resemble those ascribed to Bcl-2; however, the absence of sequence similarity to Bcl-2 or any other known cell death suppressors suggests that vMIA defines a previously undescribed class of anti-apoptotic proteins.

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

“…Alternative processing of HCMV UL37 immediate-early (IE) pre-mRNA, one of the first viral products produced during infection, predominantly generates the unspliced UL37 exon 1 (UL37x1) RNA and 10 UL37 alternatively spliced RNAs (1,18,21,47,50). These transcripts are predicted to encode six UL37 protein isoforms (1,18,21).…”

Latent Epstein–Barr virus (EBV) infection and cytomegalovirus (CMV) infection in synovial tissue of autoimmune chronic arthritis determined by RNA- and DNA-in situ hybridization

“…One feature of CMV infection is the upregulation of a number of cellular proteins, among them transcription factors and DNA replicating enzymes. 31,32 Several human CMV encoded proteins have been shown to inhibit apoptosis, 33,34 and CMV infection enhances the transactivation function of NFkappaB, which activates genes involved in apoptosis inhibition. 31 Molecular Detection of relevant synovial virus infections defined by EBER1/2-positive synovial cells or a high number of infiltrating lymphocytic cells for EBV, CMV-DNA detection in synovial cells for CMV, and detection of a relevant number of B19-VP1/VP2-protein positive cells (several or numerous as opposed to single positive cells) for B19.…”

Infection of APC by Human Cytomegalovirus Controlled Through Recognition of Endogenous Nuclear Immediate Early Protein 1 by Specific CD4+ T Lymphocytes

“…This may explain the absence of cytotoxicity when endogenous presentation, possibly resulting in lower amounts of presented IE1, was involved. Alternatively, inhibitors of apoptosis encoded by CMV (48,49) may prevent cytotoxicity in the context of the kinetics of endogenous presentation while readily available soluble IE1 in crude virus inoculum may induce CD4 ϩ T cell cytotoxicity before anti-apoptotic proteins are produced. This is the first observation of specific recognition of CMVinfected cells by CD4 ϩ T cells.…”