RESUMO
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.
Assuntos
Infecções por Adenoviridae/imunologia , Adenoviridae/patogenicidade , Proteínas E3 de Adenovirus/metabolismo , Endorribonucleases/metabolismo , Regulação Viral da Expressão Gênica/imunologia , Proteínas Serina-Treonina Quinases/metabolismo , Células A549 , Adenoviridae/genética , Adenoviridae/imunologia , Infecções por Adenoviridae/genética , Infecções por Adenoviridae/virologia , Proteínas E1A de Adenovirus/genética , Doença Crônica , Retículo Endoplasmático/metabolismo , Endorribonucleases/genética , Técnicas de Silenciamento de Genes , Técnicas de Inativação de Genes , Células HeLa , Interações Hospedeiro-Patógeno/genética , Humanos , Hospedeiro Imunocomprometido , Interferon gama/genética , Interferon gama/imunologia , Interferon gama/metabolismo , Proteínas Serina-Treonina Quinases/genética , Splicing de RNA , Latência Viral , Liberação de Vírus/genética , Proteína 1 de Ligação a X-Box/genéticaRESUMO
Dysregulated endogenous retroelements (EREs) are increasingly implicated in the initiation, progression, and immune surveillance of human cancer. However, incomplete knowledge of ERE activity limits mechanistic studies. By using pan-cancer de novo transcript assembly, we uncover the extent and complexity of ERE transcription. The current assembly doubled the number of previously annotated transcripts overlapping with long-terminal repeat (LTR) elements, several thousand of which were expressed specifically in one or a few related cancer types. Exemplified in melanoma, LTR-overlapping transcripts were highly predictable, disease prognostic, and closely linked with molecularly defined subtypes. They further showed the potential to affect disease-relevant genes, as well as produce novel cancer-specific antigenic peptides. This extended view of LTR elements provides the framework for functional validation of affected genes and targets for cancer immunotherapy.