Human cytomegalovirus glycoprotein UL141 targets the TRAIL death receptors to thwart host innate antiviral defenses

Wendell Smith; Peter Tomasec; Rebecca Aicheler; Andrea Loewendorf; Ivana Nemčovičová; Eddie C.Y. Wang; Richard J. Stanton; Matt MacAuley; Paula Norris; Laure Willen; Eva Ruckova; Akio Nomoto; Pascal Schneider; Gabriele Hahn; Dirk M. Zajonc; Carl F. Ware; Gavin W.G. Wilkinson; Chris A. Benedict

doi:10.1016/j.chom.2013.02.003

Human cytomegalovirus glycoprotein UL141 targets the TRAIL death receptors to thwart host innate antiviral defenses

Wendell Smith, Peter Tomasec, Rebecca Aicheler, Andrea Loewendorf, Ivana Nemčovičová, Eddie C.Y. Wang, Richard J. Stanton, Matt MacAuley, Paula Norris, Laure Willen, Eva Ruckova, Akio Nomoto, Pascal Schneider, Gabriele Hahn, Dirk M. Zajonc, Carl F. Ware, Gavin W.G. Wilkinson^*, Chris A. Benedict

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

79 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	324-335
Number of pages	12
Journal	Cell Host and Microbe
Volume	13
Issue number	3
DOIs	https://doi.org/10.1016/j.chom.2013.02.003
Publication status	Published - 13 Mar 2013
Externally published	Yes

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Smith, W., Tomasec, P., Aicheler, R., Loewendorf, A., Nemčovičová, I., Wang, E. C. Y., Stanton, R. J., MacAuley, M., Norris, P., Willen, L., Ruckova, E., Nomoto, A., Schneider, P., Hahn, G., Zajonc, D. M., Ware, C. F., Wilkinson, G. W. G., & Benedict, C. A. (2013). Human cytomegalovirus glycoprotein UL141 targets the TRAIL death receptors to thwart host innate antiviral defenses. Cell Host and Microbe, 13(3), 324-335. https://doi.org/10.1016/j.chom.2013.02.003

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title = "Human cytomegalovirus glycoprotein UL141 targets the TRAIL death receptors to thwart host innate antiviral defenses",

abstract = "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.",

author = "Wendell Smith and Peter Tomasec and Rebecca Aicheler and Andrea Loewendorf and Ivana Nem{\v c}ovi{\v c}ov{\'a} and Wang, {Eddie C.Y.} and Stanton, {Richard J.} and Matt MacAuley and Paula Norris and Laure Willen and Eva Ruckova and Akio Nomoto and Pascal Schneider and Gabriele Hahn and Zajonc, {Dirk M.} and Ware, {Carl F.} and Wilkinson, {Gavin W.G.} and Benedict, {Chris A.}",

year = "2013",

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doi = "10.1016/j.chom.2013.02.003",

language = "English",

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Smith, W, Tomasec, P, Aicheler, R, Loewendorf, A, Nemčovičová, I, Wang, ECY, Stanton, RJ, MacAuley, M, Norris, P, Willen, L, Ruckova, E, Nomoto, A, Schneider, P, Hahn, G, Zajonc, DM, Ware, CF, Wilkinson, GWG & Benedict, CA 2013, 'Human cytomegalovirus glycoprotein UL141 targets the TRAIL death receptors to thwart host innate antiviral defenses', Cell Host and Microbe, vol. 13, no. 3, pp. 324-335. https://doi.org/10.1016/j.chom.2013.02.003

TY - JOUR

T1 - Human cytomegalovirus glycoprotein UL141 targets the TRAIL death receptors to thwart host innate antiviral defenses

AU - Smith, Wendell

AU - Tomasec, Peter

AU - Aicheler, Rebecca

AU - Loewendorf, Andrea

AU - Nemčovičová, Ivana

AU - Wang, Eddie C.Y.

AU - Stanton, Richard J.

AU - MacAuley, Matt

AU - Norris, Paula

AU - Willen, Laure

AU - Ruckova, Eva

AU - Nomoto, Akio

AU - Schneider, Pascal

AU - Hahn, Gabriele

AU - Zajonc, Dirk M.

AU - Ware, Carl F.

AU - Wilkinson, Gavin W.G.

AU - Benedict, Chris A.

PY - 2013/3/13

Y1 - 2013/3/13

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AB - 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.

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SN - 1931-3128

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SP - 324

EP - 335

JO - Cell Host and Microbe

JF - Cell Host and Microbe

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ER -

Human cytomegalovirus glycoprotein UL141 targets the TRAIL death receptors to thwart host innate antiviral defenses

Abstract

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