An HIV feedback resistor: auto-regulatory circuit deactivator and noise buffer.
Animal viruses (e.g., lentiviruses and herpesviruses) use transcriptional positive feedback (i.e., transactivation) to regulate their gene expression. But positive-feedback circuits are inherently unstable when turned off, which presents a particular dilemma for latent viruses that lack transcriptio...
| Main Authors: | , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2007-01-01
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| Series: | PLoS Biology |
| Online Access: | http://europepmc.org/articles/PMC1717016?pdf=render |
| _version_ | 1818999531432312832 |
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| author | Leor S Weinberger Thomas Shenk |
| author_facet | Leor S Weinberger Thomas Shenk |
| author_sort | Leor S Weinberger |
| collection | DOAJ |
| description | Animal viruses (e.g., lentiviruses and herpesviruses) use transcriptional positive feedback (i.e., transactivation) to regulate their gene expression. But positive-feedback circuits are inherently unstable when turned off, which presents a particular dilemma for latent viruses that lack transcriptional repressor motifs. Here we show that a dissipative feedback resistor, composed of enzymatic interconversion of the transactivator, converts transactivation circuits into excitable systems that generate transient pulses of expression, which decay to zero. We use HIV-1 as a model system and analyze single-cell expression kinetics to explore whether the HIV-1 transactivator of transcription (Tat) uses a resistor to shut off transactivation. The Tat feedback circuit was found to lack bi-stability and Tat self-cooperativity but exhibited a pulse of activity upon transactivation, all in agreement with the feedback resistor model. Guided by a mathematical model, biochemical and genetic perturbation of the suspected Tat feedback resistor altered the circuit's stability and reduced susceptibility to molecular noise, in agreement with model predictions. We propose that the feedback resistor is a necessary, but possibly not sufficient, condition for turning off noisy transactivation circuits lacking a repressor motif (e.g., HIV-1 Tat). Feedback resistors may be a paradigm for examining other auto-regulatory circuits and may inform upon how viral latency is established, maintained, and broken. |
| first_indexed | 2024-12-20T22:18:54Z |
| format | Article |
| id | doaj.art-4cfc8082ad454a829bc7fb9a9241ede1 |
| institution | Directory Open Access Journal |
| issn | 1544-9173 1545-7885 |
| language | English |
| last_indexed | 2024-12-20T22:18:54Z |
| publishDate | 2007-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Biology |
| spelling | doaj.art-4cfc8082ad454a829bc7fb9a9241ede12022-12-21T19:24:59ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852007-01-0151e910.1371/journal.pbio.0050009An HIV feedback resistor: auto-regulatory circuit deactivator and noise buffer.Leor S WeinbergerThomas ShenkAnimal viruses (e.g., lentiviruses and herpesviruses) use transcriptional positive feedback (i.e., transactivation) to regulate their gene expression. But positive-feedback circuits are inherently unstable when turned off, which presents a particular dilemma for latent viruses that lack transcriptional repressor motifs. Here we show that a dissipative feedback resistor, composed of enzymatic interconversion of the transactivator, converts transactivation circuits into excitable systems that generate transient pulses of expression, which decay to zero. We use HIV-1 as a model system and analyze single-cell expression kinetics to explore whether the HIV-1 transactivator of transcription (Tat) uses a resistor to shut off transactivation. The Tat feedback circuit was found to lack bi-stability and Tat self-cooperativity but exhibited a pulse of activity upon transactivation, all in agreement with the feedback resistor model. Guided by a mathematical model, biochemical and genetic perturbation of the suspected Tat feedback resistor altered the circuit's stability and reduced susceptibility to molecular noise, in agreement with model predictions. We propose that the feedback resistor is a necessary, but possibly not sufficient, condition for turning off noisy transactivation circuits lacking a repressor motif (e.g., HIV-1 Tat). Feedback resistors may be a paradigm for examining other auto-regulatory circuits and may inform upon how viral latency is established, maintained, and broken.http://europepmc.org/articles/PMC1717016?pdf=render |
| spellingShingle | Leor S Weinberger Thomas Shenk An HIV feedback resistor: auto-regulatory circuit deactivator and noise buffer. PLoS Biology |
| title | An HIV feedback resistor: auto-regulatory circuit deactivator and noise buffer. |
| title_full | An HIV feedback resistor: auto-regulatory circuit deactivator and noise buffer. |
| title_fullStr | An HIV feedback resistor: auto-regulatory circuit deactivator and noise buffer. |
| title_full_unstemmed | An HIV feedback resistor: auto-regulatory circuit deactivator and noise buffer. |
| title_short | An HIV feedback resistor: auto-regulatory circuit deactivator and noise buffer. |
| title_sort | hiv feedback resistor auto regulatory circuit deactivator and noise buffer |
| url | http://europepmc.org/articles/PMC1717016?pdf=render |
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