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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.

Cutaneous T-cell lymphoma (CTCL) remains a challenging disease due to its significant heterogeneity, therapy resistance, and relentless progression. Multi-omics technologies offer the potential to provide uniquely precise views of disease progression and response to therapy. We present here a comprehensive multi-omics view of CTCL clonal evolution, incorporating exome, whole genome, epigenome, bulk-, single cell (sc) VDJ-, and scRNA-sequencing of 114 clinically annotated serial skin, peripheral blood, and lymph node samples from 35 CTCL patients. We leveraged this extensive dataset to define the molecular underpinnings of CTCL progression in individual patients at single cell resolution with the goal of identifying clinically useful biomarkers and therapeutic targets. Our studies identified a large number of recurrent progression-associated clonal genomic alterations; we highlight mutation of CCR4, PI3K signaling, and PD-1 checkpoint pathways as evasion tactics deployed by malignant T cells. We also identified a gain of function mutation in STAT3 (D661Y) and demonstrated by CUT&RUN-seq that it enhances binding to transcription start sites of genes in Rho GTPase pathways, which we previously reported to have activated chromatin and increased expression in HDACi-resistant CTCL. These data provide further support for a previously unrecognized role for Rho GTPase pathway dysregulation in CTCL progression. A striking number of progression-associated mutations occurred in chromatin methylation modifiers, including EZH2, suggesting that EZH1/2 inhibition may also benefit patients with CTCL. Knowledge of these molecular changes should be leveraged for improved disease monitoring, biomarker-informed clinical trial design, and new therapeutic strategies in this challenging and incurable cancer.

Ebola virus (EBOV) is a non-segmented, negative-sense virus (NNSV) with a single-stranded RNA genome. EBOV encodes for a limited number of proteins and thus depends on host factors to facilitate viral replication and pathogenesis. Of the virus-encoded proteins, multifunctional EBOV VP35 (eVP35) is necessary for host immune evasion and viral RNA synthesis. Previous proteomics studies identified an interaction between eVP35 and the host E3 ubiquitin ligase Mindbomb 2 (MIB2). Here, we show how a previously uncharacterized NNLNS motif (residues 201-205) within eVP35 serves as a binding site for MIB2. This motif is critical for eVP35-dependent inhibition of MIB2-mediated IFN induction. It is also important for EBOV RNA synthesis as MIB2 binding to eVP35 inhibited EBOV minigenome activity. Altogether, these findings highlight the importance of the eVP35 protein and the role of host factors in EBOV infection.