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.
Highlights
Persistent viruses cause chronic disease, and threaten the lives of immunosuppressed individuals
We explored if IRE1α–X-box binding protein-1 (XBP1) controlled persistent AdV infections of HDFTERT cells
We showed that the E3-19K glycoprotein of species C2/5 but not of the divergent D8 AdV is necessary and sufficient to selectively activate IRE1α, but not protein kinase R-like ER kinase (PERK), activating transcription factor 6 (ATF6), and regulated IRE1α-dependent decay (RIDD), see ref
Summary
Persistent viruses cause chronic disease, and threaten the lives of immunosuppressed individuals. Enveloped viruses, including influenza virus and herpes viruses subvert the UPR for the synthesis of viral glycoproteins[4,5,6] They involve three transmembrane sensors in the ER, the inositol-requiring enzyme 1 (IRE1), activating transcription factor 6 (ATF6/p90), and protein kinase RNA-like ER kinase (PERK). IRE1α, ATF6, and PERK enhance the levels of the transcription factors XBP1s, ATF6/p50, and ATF4, respectively, and upregulate gene expression of chaperones and slow down protein translation restoring ER homeostasis[7,8,9,10]. E1A proteins interact with numerous host proteins on double-stranded DNA, and control host transcription, the cell cycle, DNA replication, and suppress the expression of IFN-stimulated genes They activate all early AdV promoters, including those controlling E1B, E2, E3, and E4, and drive viral replication[21,26,27]. The E3B region encodes RIDα and RIDβ blocking apoptosis mediated through tumor necrosis factor (TNF), Fas ligand, and TRAIL signaling
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