Abstract
SummaryDeath receptors (DRs) of the TNFR superfamily contribute to antiviral immunity by promoting apoptosis and regulating immune homeostasis during infection, and viral inhibition of DR signaling can alter immune defenses. Here we identify the human cytomegalovirus (HCMV) UL141 glycoprotein as necessary and sufficient to restrict TRAIL DR function. Despite showing no primary sequence homology to TNF family cytokines, UL141 binds the ectodomains of both human TRAIL DRs with affinities comparable to the natural ligand TRAIL. UL141 binding promotes intracellular retention of the DRs, thus protecting virus infected cells from TRAIL and TRAIL-dependent NK cell-mediated killing. The identification of UL141 as a herpesvirus modulator of the TRAIL DRs strongly implicates this pathway as a regulator of host defense to HCMV and highlights UL141 as a pleiotropic inhibitor of NK cell effector function.
Highlights
Tumor necrosis factor (TNF) family cytokines are crucial in providing protection against virus infections through their regulation of cell death and survival (Benedict, 2003)
Death receptors (DRs) of the TNFR superfamily contribute to antiviral immunity by promoting apoptosis and regulating immune homeostasis during infection, and viral inhibition of DR signaling can alter immune defenses
Despite showing no primary sequence homology to TNF family cytokines, UL141 binds the ectodomains of both human TRAIL DRs with affinities comparable to the natural ligand TRAIL
Summary
Tumor necrosis factor (TNF) family cytokines are crucial in providing protection against virus infections through their regulation of cell death and survival (Benedict, 2003). The large DNA herpesviruses all establish lifelong infection, and they employ many strategies to modulate cellular apoptotic signaling pathways. These range from restricting ligand-receptor interactions to blocking caspase activation and activating prosurvival pathways (Loewendorf and Benedict, 2010; Mocarski et al, 2012; Rahman and McFadden, 2006), impacting the duration of infection and the magnitude of downstream immune responses. HCMV has become a paradigm for immune modulation, and its study is proving insightful in characterizing the key mechanisms responsible for regulating human NK cell function. UL141 is a type I transmembrane glycoprotein encoded within the the right hand end of the UL (UL/b0) region of the HCMV genome that was lost from the commonly-used laboratory strains AD169 and Towne during in vitro passage
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