Human cytomegalovirus suppresses Fas expression and function

Abstract

Human cytomegalovirus (HCMV) is known to evade extrinsic pro-apoptotic pathways not only by downregulating cell surface expression of the death receptors TNFR1, TRAIL receptor 1 (TNFRSF10A) and TRAIL receptor 2 (TNFRSF10B), but also by impeding downstream signalling events. Fas (CD95/APO-1/TNFRSF6) also plays a prominent role in apoptotic clearance of virusinfected cells, so its fate in HCMV-infected cells needs to be addressed. Here, we show that cell surface expression of Fas was suppressed in HCMV-infected fibroblasts from 24 h onwards through the late phase of productive infection, and was dependent on de novo virus-encoded gene expression but not virus DNA replication. Significant levels of the fully glycosylated (endoglycosidase-H-resistant) Fas were retained within HCMV-infected cells throughout the infection within intracellular membranous structures. HCMV infection provided cells with a high level of protection against Fas-mediated apoptosis. Downregulation of Fas was observed with HCMV strains AD169, FIX, Merlin and TB40.

Cross-Species Rhesus Cytomegalovirus Infection of Cynomolgus Macaques

“…Interestingly, UL37 has been previously implicated in controlling species specific cell tropism between human and mouse CMV as insertion of HCMV UL37 enables MCMV to grow in human cells [6]. Moreover, recent evidence indicates that microRNAs expressed by HCMV can exert anti-apoptotic effects [54], and other mechanisms of CMV apoptosis suppression are currently being explored [55–59]. Thus, RM-specific compensatory mechanism might explain the species-specific dependence on UL36 for infection of CM but not RM.…”

Die Another Day: Inhibition of Cell Death Pathways by Cytomegalovirus

“…Multiple proteins involved in immune recognition including DR are downregulated following infection with CMV. Cell surface expression of the Fas and TNF receptors are reduced following infection with HCMV or MCMV, respectively [ 101 , 102 ]. Surprisingly, the UL138 protein encoded by HCMV increases TNFR1 levels at the cell surface [ 103 , 104 ].…”

Current and Emerging Biomarkers of Cell Death in Human Disease

“…Death receptors are membrane-bound protein complexes that can activate an intracellular signaling cascade by binding specific ligands and play a central role in apoptosis [ 12 , 38 ]. Death receptors belong to the TNFR (tumor necrosis factor receptor) superfamily whose members typically include Fas (also known as CD95, APO-1, and TNFRSF6), TNFR1 (also known as CD120a, p55, and p60), TRAILR1 (also known as DR4, CD261, and APO-2), and TRAILR2 (also known as DR5, KILLER, and CD262) [ 39 ]. These death receptors contain a cytoplasmic region of ~80 residues termed the death domain (DD) which provides the capacity for protein-protein interactions with other molecules [ 40 ].…”