HDAC5 enhances IRF3 activation and is targeted for degradation by protein C6 from orthopoxviruses including Monkeypox virus and Variola virus.

Histone deacetylases (HDACs) regulate gene expression and innate immunity. Previously, we showed that HDAC5 is degraded during Vaccinia virus (VACV) infection and is a restriction factor for VACV and herpes simplex virus type 1. Here, we report that HDAC5 promotes interferon regulatory factor 3 (IRF3) activation downstream of Toll-IL-1 receptor (TIR) domain-containing adaptor molecule-1 or Sendai virus-mediated stimulation without requiring HDAC activity. Loss of HDAC5-mediated IRF3 activation is restored by re-introduction of HDAC5 but not HDAC1 or HDAC4. The antiviral activity of HDAC5 is antagonized by VACV protein C6 and orthologs from the orthopoxviruses cowpox, rabbitpox, camelpox, monkeypox, and variola. Infection by many of these viruses induces proteasomal degradation of HDAC5, and expression of C6 alone can induce HDAC5 degradation. Mechanistically, C6 binds to the dimerization domain of HDAC5 and prevents homodimerization and heterodimerization with HDAC4. Overall, this study describes HDAC5 as a positive regulator of IRF3 activation and provides mechanistic insight into how the poxviral protein C6 binds to HDAC5 to antagonize its function.

Filamin B restricts vaccinia virus spread and is targeted by vaccinia virus protein C4.

Vaccinia virus (VACV) is a large DNA virus that encodes scores of proteins that modulate the host immune response. VACV protein C4 is one such immunomodulator known to inhibit the activation of both the NF-κB signaling cascade and the DNA-PK-mediated DNA sensing pathway. Here, we show that the N-terminal region of C4, which neither inhibits NF-κB nor mediates interaction with DNA-PK, still contributes to virus virulence. Furthermore, this domain interacts directly and with high affinity to the C-terminal domain of filamin B (FLNB). FLNB is a large actin-binding protein that stabilizes the F-actin network and is implicated in other cellular processes. Deletion of FLNB from cells results in larger VACV plaques and increased infectious viral yield, indicating that FLNB restricts VACV spread. These data demonstrate that C4 has a new function that contributes to virulence and engages the cytoskeleton. Furthermore, we show that the cytoskeleton performs further previously uncharacterized functions during VACV infection. IMPORTANCE: Vaccinia virus (VACV), the vaccine against smallpox and monkeypox, encodes many proteins to counteract the host immune response. Investigating these proteins provides insights into viral immune evasion mechanisms and thereby indicates how to engineer safer and more immunogenic VACV-based vaccines. Here, we report that the N-terminal domain of VACV protein C4 interacts directly with the cytoskeletal protein filamin B (FLNB), and this domain of C4 contributes to virus virulence. Furthermore, VACV replicates and spreads better in cells lacking FLNB, thus demonstrating that FLNB has antiviral activity. VACV utilizes the cytoskeleton for movement within and between cells; however, previous studies show no involvement of C4 in VACV replication or spread. Thus, C4 associates with FLNB for a different reason, suggesting that the cytoskeleton has further uncharacterized roles during virus infection.

Reproducibility in systems biology modelling.

Reproducibility of scientific results is a key element of science and credibility. The lack of reproducibility across many scientific fields has emerged as an important concern. In this piece, we assess mathematical model reproducibility and propose a scorecard for improving reproducibility in this field.

BioModels-15 years of sharing computational models in life science.

Computational modelling has become increasingly common in life science research. To provide a platform to support universal sharing, easy accessibility and model reproducibility, BioModels (https://www.ebi.ac.uk/biomodels/), a repository for mathematical models, was established in 2005. The current BioModels platform allows submission of models encoded in diverse modelling formats, including SBML, CellML, PharmML, COMBINE archive, MATLAB, Mathematica, R, Python or C++. The models submitted to BioModels are curated to verify the computational representation of the biological process and the reproducibility of the simulation results in the reference publication. The curation also involves encoding models in standard formats and annotation with controlled vocabularies following MIRIAM (minimal information required in the annotation of biochemical models) guidelines. BioModels now accepts large-scale submission of auto-generated computational models. With gradual growth in content over 15 years, BioModels currently hosts about 2000 models from the published literature. With about 800 curated models, BioModels has become the world's largest repository of curated models and emerged as the third most used data resource after PubMed and Google Scholar among the scientists who use modelling in their research. Thus, BioModels benefits modellers by providing access to reliable and semantically enriched curated models in standard formats that are easy to share, reproduce and reuse.