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

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 v...

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Published in:Nature communications Vol. 16; no. 1; pp. 2883 - 14
Main Authors: Kalita, Parismita, Khatavkar, Oam, Uwase, Grace, Korshunova, Yulia, Hu, Yuying, Wagner, Nicole D., Xu, Jian, Pan, Jiehong, Nix, Jay C., Gross, Michael L., Brody, Steven L., Borek, Dominika, Amarasinghe, Gaya K., Payton, Jacqueline E., Leung, Daisy W.
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 25.03.2025
Nature Publishing Group
Nature Portfolio
Subjects:
38/91
60 APPLIED LIFE SCIENCES
631/326/596/2557
631/45/612/1256
631/535/1266
82/16
82/80
82/83
96/109
Activating transcription factor 3
Activating Transcription Factor 3 - genetics
Activating Transcription Factor 3 - metabolism
Crystal structure
Crystallography, X-Ray
DNA-directed RNA polymerase
Gene regulation
Heterogeneity
Host-Pathogen Interactions
Humanities and Social Sciences
Humans
Interfaces
Mediator Complex - chemistry
Mediator Complex - genetics
Mediator Complex - metabolism
Models, Molecular
multidisciplinary
Protein Binding
Protein structure
Respiratory syncytial virus
Respiratory Syncytial Virus Infections - genetics
Respiratory Syncytial Virus Infections - metabolism
Respiratory Syncytial Virus Infections - virology
Respiratory Syncytial Virus, Human - genetics
Respiratory Syncytial Virus, Human - metabolism
Ribonucleic acid
RNA
RNA polymerase
RNA polymerase II
Science
Science (multidisciplinary)
Structural analysis
Transcription factors
Transcription, Genetic
Viral infections
Viral Nonstructural Proteins - chemistry
Viral Nonstructural Proteins - genetics
Viral Nonstructural Proteins - metabolism
Viruses
ISSN:2041-1723, 2041-1723
Online Access:Get full text
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Summary: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. This study provides the structural and biochemical characterization of the RSV NS1/MED25 ACID complex, revealing how RSV exploits fuzzy interfaces between coactivators and transcription factors, including ATF3, to modulate host gene transcription.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
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USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF)
AC02-05CH11231
None
National Institutes of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-025-58216-4