Molecular basis for human respiratory syncytial virus transcriptional regulator NS1 interactions with MED25

Parismita Kalita, Oam Khatavkar, Grace Uwase, Yulia Korshunova, Yuying Hu, Nicole D. Wagner, Jian Xu, Jiehong Pan, Jay C. Nix, Michael L. Gross, Steven L. Brody, Dominika Borek, Gaya K. Amarasinghe, Jacqueline E. Payton and Daisy W. Leung ()
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Parismita Kalita: Washington University School of Medicine
Oam Khatavkar: Washington University School of Medicine
Grace Uwase: Washington University School of Medicine
Yulia Korshunova: Washington University School of Medicine
Yuying Hu: Washington University School of Medicine
Nicole D. Wagner: Washington University School of Medicine
Jian Xu: Washington University School of Medicine
Jiehong Pan: Washington University School of Medicine
Jay C. Nix: Lawrence Berkeley National Laboratory
Michael L. Gross: Washington University in St. Louis
Steven L. Brody: Washington University School of Medicine
Dominika Borek: University of Texas Southwestern Medical Center
Gaya K. Amarasinghe: Washington University School of Medicine
Jacqueline E. Payton: Washington University School of Medicine
Daisy W. Leung: Washington University School of Medicine

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract The Mediator complex facilitates interactions between transcription factors and RNA polymerase II, a process that is required for host gene transcription, including in response to viral infections. Among the many subunits in the Mediator complex, the MED25 subunit has been shown to be a target for viral activators during infection. Here we provide the molecular basis for the interaction between human respiratory syncytial virus (hRSV) nonstructural 1 protein (NS1) and the activator interaction domain (ACID) of MED25. The X-ray crystal structure of the complex revealed that NS1 straddles and binds two faces of MED25 ACID. This interaction is distinct from previously known viral activators. Importantly, our data support the conformational flexibility of viral transcriptional regulators. Furthermore, ChIP-seq and RNA-seq analysis identified the ATF3 transcription factor and a role for NS1/Mediator/ATF3 interaction in host gene regulation in hRSV infections. Our findings provide a molecular basis for hRSV NS1-based regulation of host gene transcription and reveal how viruses exploit the conformational heterogeneity at fuzzy transcription activator interfaces.

Date: 2025
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DOI: 10.1038/s41467-025-58216-4

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