The UPR sensor IRE1α and the adenovirus E3-19K glycoprotein sustain persistent and lytic infections

Vibhu Prasad, Maarit Suomalainen, Yllza Jasiqi, Silvio Hemmi, Patrick Hearing, Louise Hosie, Hans-Gerhard Burgert and Urs F. Greber ()
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Vibhu Prasad: University of Zurich
Maarit Suomalainen: University of Zurich
Yllza Jasiqi: University of Zurich
Silvio Hemmi: University of Zurich
Patrick Hearing: Stony Brook University
Louise Hosie: University of Warwick, School of Life Sciences
Hans-Gerhard Burgert: University of Warwick, School of Life Sciences
Urs F. Greber: University of Zurich

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract Persistent viruses cause chronic disease, and threaten the lives of immunosuppressed individuals. Here, we elucidate a mechanism supporting the persistence of human adenovirus (AdV), a virus that can kill immunosuppressed patients. Cell biological analyses, genetics and chemical interference demonstrate that one of five AdV membrane proteins, the E3-19K glycoprotein specifically triggers the unfolded protein response (UPR) sensor IRE1α in the endoplasmic reticulum (ER), but not other UPR sensors, such as protein kinase R-like ER kinase (PERK) and activating transcription factor 6 (ATF6). The E3-19K lumenal domain activates the IRE1α nuclease, which initiates mRNA splicing of X-box binding protein-1 (XBP1). XBP1s binds to the viral E1A-enhancer/promoter sequence, and boosts E1A transcription, E3-19K levels and lytic infection. Inhibition of IRE1α nuclease interrupts the five components feedforward loop, E1A, E3-19K, IRE1α, XBP1s, E1A enhancer/promoter. This loop sustains persistent infection in the presence of the immune activator interferon, and lytic infection in the absence of interferon.

Date: 2020
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DOI: 10.1038/s41467-020-15844-2

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