Feedback-mediated signal conversion promotes viral fitness.

Proceedings of the National Academy of Sciences of the United States of America
Noam VardiLeor S Weinberger

Abstract

A fundamental signal-processing problem is how biological systems maintain phenotypic states (i.e., canalization) long after degradation of initial catalyst signals. For example, to efficiently replicate, herpesviruses (e.g., human cytomegalovirus, HCMV) rapidly counteract cell-mediated silencing using transactivators packaged in the tegument of the infecting virion particle. However, the activity of these tegument transactivators is inherently transient-they undergo immediate proteolysis but delayed synthesis-and how transient activation sustains lytic viral gene expression despite cell-mediated silencing is unclear. By constructing a two-color, conditional-feedback HCMV mutant, we find that positive feedback in HCMV's immediate-early 1 (IE1) protein is of sufficient strength to sustain HCMV lytic expression. Single-cell time-lapse imaging and mathematical modeling show that IE1 positive feedback converts transient transactivation signals from tegument pp71 proteins into sustained lytic expression, which is obligate for efficient viral replication, whereas attenuating feedback decreases fitness by promoting a reversible silenced state. Together, these results identify a regulatory mechanism enabling herpesviruses to sustain ex...Continue Reading

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Citations

Jun 22, 2019·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Maike M K Hansen, Leor S Weinberger
Apr 1, 2020·Frontiers in Cellular and Infection Microbiology·Robert F Kalejta, Emily R Albright
Jul 8, 2020·Proceedings of the National Academy of Sciences of the United States of America·Sonali ChaturvediLeor S Weinberger
Jul 17, 2020·Frontiers in Cellular and Infection Microbiology·Sonali ChaturvediLeor Weinberger
Mar 9, 2021·Angewandte Chemie·Xinlong Fan, Andreas Walther
Jul 27, 2021·Frontiers in Cellular and Infection Microbiology·Emma L Poole, Michael M Nevels

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