Human Cytomegalovirus Glycoprotein UL141 Targets the TRAIL Death Receptors to Thwart Host Innate Antiviral Defenses

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• 作者：Wendell Smith¹ ; ⁹ ; Peter Tomasec² ; ⁹ ; Rebecca Aicheler² ; ⁹ ; Andrea Loewendorf¹ ; ⁸ ; Ivana Nem?ovi?ová ; ¹ ; Eddie C.Y. Wang² ; Richard J. Stanton² ; Matt Macauley³ ; Paula Norris³ ; Laure Willen⁴ ; Eva Ruckova⁵ ; Akio Nomoto⁶ ; Pascal Schneider⁴ ; Gabriele Hahn⁷ ; Dirk M. Zajonc¹ ; Carl F. Ware³ ; Gavin W.G. Wilkinson² ; ¹⁰ ; ^{wilkinsongw1@cf.ac.uk} ; Chris A. Benedict¹ ; ¹⁰ ; ^{benedict@liai.org}
• 刊名：Cell Host Microbe
• 出版年：2013
• 出版时间：13 March, 2013
• 年：2013
• 卷：13
• 期：3
• 页码：324-335
• 全文大小：1447 K

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Summary

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. 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.