Repression of Viral Gene Expression and Replication by the Unfolded Protein Response Effector XBP1u
| Autor: | Florian Hinte, Boaz Tirosh, Wolfram Brune, Eelco van Anken |
|---|---|
| Přispěvatelé: | Hinte, F., Van Anken, E., Tirosh, B., Brune, W. |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Gene Expression Regulation
Viral X-Box Binding Protein 1 Muromegalovirus XBP1 Mouse XBP1u QH301-705.5 Science Repressor Biology Protein Serine-Threonine Kinases Virus Replication General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Unfolded protein response/transcription factor/XBP1u/ATF6/cytomegalovirus Humans murid herpesvirus 1 Biology (General) ATF6 Psychological repression Transcription factor transcription factor 030304 developmental biology 0303 health sciences Microbiology and Infectious Disease General Immunology and Microbiology Effector Binding protein General Neuroscience 030302 biochemistry & molecular biology Membrane Proteins General Medicine Cell Biology unfolded protein response 3. Good health Cell biology Virus Unfolded Protein Response Unfolded protein response Medicine Signal transduction Research Article Signal Transduction |
| Zdroj: | eLife eLife, Vol 9 (2020) |
| DOI: | 10.1101/763227 |
| Popis: | The unfolded protein response (UPR) is a cellular homeostatic circuit regulating protein synthesis and processing in the ER by three ER-to-nucleus signaling pathways. One pathway is triggered by the inositol-requiring enzyme 1 (IRE1), which splices the X-box binding protein 1 (Xbp1) mRNA, thereby enabling expression of XBP1s. Another UPR pathway activates the activating transcription factor 6 (ATF6). Here we show that murine cytomegalovirus (MCMV), a prototypic β-herpesvirus, harnesses the UPR to regulate its own life cycle. MCMV activates the IRE1-XBP1 pathway early post infection to relieve repression by XBP1u, the product of the unspliced Xbp1 mRNA. XBP1u inhibits viral gene expression and replication by blocking the activation of the viral major immediate-early promoter by XBP1s and ATF6. These findings reveal a redundant function of XBP1s and ATF6 as activators of the viral life cycle, and an unexpected role of XBP1u as a potent repressor of both XBP1s and ATF6-mediated activation. eLife digest Cells survive by making many different proteins that each carry out specific tasks. To work correctly, each protein must be made and then folded into the right shape. Cells carefully monitor protein folding because unfolded proteins can compromise their viability. A protein called XBP1 is important in controlling how cells respond to unfolded proteins. Normally, cells contain a form of this protein called XBP1u, while increasing numbers of unfolded proteins trigger production of a form called XBP1s. The change from one form to the other is activated by a protein called IRE1. Viruses often manipulate stress responses like the unfolded protein response to help take control of the cell and produce more copies of the virus. Murine cytomegalovirus, which is known as MCMV for short, is a herpes-like virus that infects mice; it stops IRE1 activation and XBP1s production during the later stages of infection. However, research had shown that the unfolded protein response was triggered for a short time at an early stage of infection with MCMV, and it was unclear why this might be. Hinte et al. studied the effect of MCMV on cells grown in the laboratory. The experiments showed that a small dose of cell stress, namely activating the unfolded protein response briefly during early infection, helps to activate genes from the virus that allow it to take over the cell. Together, XBP1s and another protein called ATF6 help to switch on the viral genes. The virus also triggers IRE1 helping to reduce the levels of XBP1u, which could slow down the infection. Later, suppressing the unfolded protein response allows copies of the virus to be made faster to help spread the infection. These findings reveal new details of how viruses precisely manipulate their host cells at different stages of infection. These insights could lead to new ways to manage or prevent viral infections. |
| Databáze: | OpenAIRE |
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