Hantavirus Inhibits TRAIL-Mediated Killing of Infected Cells by Downregulating Death Receptor 5

Carles Solà-Riera, Shawon Gupta, Kimia T Maleki, Patricia González-Rodriguez, Dalel Saidi, Christine L Zimmer, Sindhu Vangeti, Laura Rivino, Yee-Sin Leo, David Chien Lye, Paul A MacAry, Clas Ahlm, Anna Smed-Sörensen, Bertrand Joseph, Niklas K Björkström, Hans-Gustaf Ljunggren, Jonas Klingström

Research output: Contribution to journalArticle (Academic Journal)peer-review

Abstract

Cytotoxic lymphocytes normally kill virus-infected cells by apoptosis induction. Cytotoxic granule-dependent apoptosis induction engages the intrinsic apoptosis pathway, whereas death receptor (DR)-dependent apoptosis triggers the extrinsic apoptosis pathway. Hantaviruses, single-stranded RNA viruses of the order Bunyavirales, induce strong cytotoxic lymphocyte responses in infected humans. Cytotoxic lymphocytes, however, are largely incapable of eradicating hantavirus-infected cells. Here, we show that the prototypic hantavirus, Hantaan virus (HTNV), induces TRAIL production but strongly inhibits TRAIL-mediated extrinsic apoptosis induction in infected cells by downregulating DR5 cell surface expression. Mechanistic analyses revealed that HTNV triggers both 26S proteasome-dependent degradation of DR5 through direct ubiquitination of DR5 and hampers DR5 transport to the cell surface. These results corroborate earlier findings, demonstrating that hantavirus also inhibits cytotoxic cell granule-dependent apoptosis induction. Together, these findings show that HTNV counteracts intrinsic and extrinsic apoptosis induction pathways, providing a defense mechanism utilized by hantaviruses to inhibit cytotoxic cell-mediated eradication of infected cells.

Original languageEnglish
Pages (from-to)2124-2139.e6
JournalCell Reports
Volume28
Issue number8
DOIs
Publication statusPublished - 20 Aug 2019

Bibliographical note

Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.

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