1. The UPR sensor IRE1α and the adenovirus E3-19K glycoprotein sustain persistent and lytic infections.
- Author
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Prasad V, Suomalainen M, Jasiqi Y, Hemmi S, Hearing P, Hosie L, Burgert HG, and Greber UF
- Subjects
- A549 Cells, Adenoviridae genetics, Adenoviridae immunology, Adenoviridae Infections genetics, Adenoviridae Infections virology, Adenovirus E1A Proteins genetics, Chronic Disease, Endoplasmic Reticulum metabolism, Endoribonucleases genetics, Gene Knockdown Techniques, Gene Knockout Techniques, HeLa Cells, Host-Pathogen Interactions genetics, Humans, Immunocompromised Host, Interferon-gamma genetics, Interferon-gamma immunology, Interferon-gamma metabolism, Protein Serine-Threonine Kinases genetics, RNA Splicing, Virus Latency, Virus Release genetics, X-Box Binding Protein 1 genetics, Adenoviridae pathogenicity, Adenoviridae Infections immunology, Adenovirus E3 Proteins metabolism, Endoribonucleases metabolism, Gene Expression Regulation, Viral immunology, Protein Serine-Threonine Kinases metabolism
- 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.
- Published
- 2020
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