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Virus-induced FoxO factor facilitates replication of human cytomegalovirus

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Abstract

Recently, it was reported that the forkhead box O (FoxO) transcription factor promotes human cytomegalovirus (HCMV) replication via direct binding to the promoters of the major immediate-early (MIE) genes, but how the FoxO factor impacts HCMV replication remains unknown. Here, it is reported that FoxO1 expression is strongly induced by HCMV infection in cells of fibroblast origin. Suppression of the FoxO1 gene by specific RNA interference significantly inhibited HCMV growth and replication, but viral DNA synthesis was not affected considerably. Interestingly, depletion or overexpression of FoxO1 had a significant effect on the expression of viral early/late transcripts. FoxO1 was found to colocalize with the pUL44 protein subunit of viral replication compartments without direct association with DNA. This study highlights how FoxO enhances HCMV gene transcription and viral replication to promote infection.

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Abbreviations

HCMV:

Human cytomegalovirus

IE:

Immediate early gene

E:

Early gene

EL:

Early-late gene

L:

Late gene

FoxO:

Forkhead box O transcription factor

BAC:

Bacterial artificial chromosome

vRC:

Viral replication compartment

EBV:

Epstein-Barr virus

HCV:

Hepatitis C virus

FoxO1–ADA:

FoxO1 containing T24A/S253D/S316A mutations

GFP:

Green fluorescent protein

ChIP:

Chromatin immunoprecipitation

IGFBP1:

Insulin-like growth factor binding protein 1

HEK293T:

Human embryonic kidney 293 T cell

MRC5:

Medical Research Council cell strain 5 (human embryonic lung fibroblasts

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Acknowledgements

I first want to thank Shaowu Huang for his generous help in this report. Furthermore, I want to extend my thanks to Dr. Yongjun Yu (University of Pennsylvania) and Dr. Yi-Chieh Perng (Washington University in St. Louis) for reading the manuscript critically. I thank all of the Herpesvirus and Molecular Virology Research Unit members for helpful discussions, Dr. Thomas Shenk for antibodies, Dr. Jay Nelson for IE1/2 antibody, and Roger Everett (University of Glasgow) for the pLKO-based lentiviral expression system.

Funding

This work was supported by a CAS-TWAS Fellowship. The funders had no role in study design, data collection, analysis, or manuscript submission.

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Authors and Affiliations

  1. College of Veterinary Medicine, University of Sulaimani, Sulaymaniyah, Iraq

    Sirwan Sleman

  2. Medical Laboratory Science, Komar University of Technology and Sciences, Sulaymaniyah, Iraq

    Sirwan Sleman

  3. Medical Laboratory Analysis, Cihan University of Sulaymaniyah, Sulaymaniyah, Iraq

    Sirwan Sleman

  4. Unit of Herpesvirus and Molecular Virology, Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China

    Sirwan Sleman

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SS performed experiments and wrote the manuscript, and he is the corresponding author.

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Sleman, S. Virus-induced FoxO factor facilitates replication of human cytomegalovirus. Arch Virol 167, 109–121 (2022). https://doi.org/10.1007/s00705-021-05279-5

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