The HSV-1 ICP4 Transcriptional Auto-Repression Circuit Functions as a Transcriptional "Accelerator" Circuit.

Frontiers in Cellular and Infection Microbiology
Sonali ChaturvediLeor Weinberger

Abstract

Herpes simplex virus-1 (HSV-1) is a significant human pathogen. Upon infection, HSV-1 expresses its immediate early (IE) genes, and the IE transcription factor ICP4 (infectious cell protein-4) plays a pivotal role in initiating the downstream gene-expression cascade. Using live-cell time-lapse fluorescence microscopy, flow cytometry, qPCR, and chromatin immunoprecipitation, we quantitatively monitored the expression of ICP4 in individual cells after infection. We find that extrinsic stimuli can accelerate ICP4 kinetics without increasing ICP4 protein or mRNA levels. The accelerated ICP4 kinetics-despite unchanged steady-state ICP4 protein or mRNA level-correlate with increased HSV-1 replicative fitness. Hence, the kinetics of ICP4 functionally mirror the kinetics of the human herpesvirus cytomegalovirus IE2 "accelerator" circuit, indicating that IE accelerator circuitry is shared among the alpha and beta herpesviruses. We speculate that this circuit motif is a common evolutionary countermeasure to throttle IE expression and thereby minimize the inherent cytotoxicity of these obligate viral transactivators.

References

Apr 1, 1975·Proceedings of the National Academy of Sciences of the United States of America·R W Honess, B Roizman
Jan 1, 1986·Proceedings of the National Academy of Sciences of the United States of America·P J Godowski, D M Knipe
Oct 15, 1993·Proceedings of the National Academy of Sciences of the United States of America·B GuN A DeLuca
Mar 18, 2008·Nature Genetics·Leor S WeinbergerMichael L Simpson
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Aug 29, 2018·Proceedings of the National Academy of Sciences of the United States of America·Noam VardiLeor S Weinberger
Dec 25, 2019·Proceedings of the National Academy of Sciences of the United States of America·Efrat M CohenOren Kobiler

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Methods Mentioned

BETA
flow
flow cytometry
immunoprecipitation
ChIP

Software Mentioned

MatLab
MathWorks

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