The UPR sensor IRE1α and the adenovirus E3-19K glycoprotein sustain persistent and lytic infections.
Vibhu PrasadMaarit SuomalainenYllza JasiqiSilvio HemmiPatrick HearingLouise HosieHans-Gerhard BurgertUrs F GreberPublished in: Nature communications (2020)
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.
Keyphrases
- transcription factor
- endoplasmic reticulum stress
- endoplasmic reticulum
- binding protein
- dna binding
- protein kinase
- end stage renal disease
- endothelial cells
- newly diagnosed
- gene expression
- ejection fraction
- signaling pathway
- single cell
- sars cov
- chronic kidney disease
- estrogen receptor
- gene therapy
- protein protein
- tyrosine kinase
- nuclear factor
- mesenchymal stem cells