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Unphosphorylated ISGF3 drives constitutive expression of interferon-stimulated genes to protect against viral infections

2017-04-25T10:50:12-07:00

Interferon (IFN)–stimulated genes (ISGs) are antiviral effectors that are induced by IFNs through the formation of a tripartite transcription factor ISGF3, which is composed of IRF9 and phosphorylated forms of STAT1 and STAT2. However, we found that IFN-independent ISG expression was detectable in immortalized cell lines, primary intestinal and liver organoids, and liver tissues. The constitutive expression of ISGs was mediated by the unphosphorylated ISGF3 (U-ISGF3) complex, consisting of IRF9 together with unphosphorylated STAT1 and STAT2. Under homeostatic conditions, STAT1, STAT2, and IRF9 were found in the nucleus. Analysis of a chromatin immunoprecipitation sequencing data set revealed that STAT1 specifically bound to the promoters of ISGs even in the absence of IFNs. Knockdown of STAT1, STAT2, or IRF9 by RNA interference led to the decreased expression of various ISGs in Huh7.5 human liver cells, which was confirmed in mouse embryonic fibroblasts (MEFs) from STAT1–/–, STAT2–/–, or IRF9–/– mice. Furthermore, decreased ISG expression was accompanied by increased replication of hepatitis C virus and hepatitis E virus. Conversely, simultaneous overexpression of all ISGF3 components, but not any single factor, induced the expression of ISGs and inhibited viral replication; however, no phosphorylated STAT1 and STAT2 were detected. A phosphorylation-deficient STAT1 mutant was comparable to the wild-type protein in mediating the IFN-independent expression of ISGs and antiviral activity, suggesting that ISGF3 works in a phosphorylation-independent manner. These data suggest that the U-ISGF3 complex is both necessary and sufficient for constitutive ISG expression and antiviral immunity under homeostatic conditions.




Papers of note in Nature 544 (7650)

2017-04-25T10:50:12-07:00

This week’s articles show that vesicle fusion proteins are involved in long-term potentiation and highlight the structural properties that contribute to functional differences between angiotensin II receptors.




Active life, active antitumor defense

2017-04-25T10:50:12-07:00

An active lifestyle in mice stimulates adrenergic signaling in the nervous system that enhances the function of antitumor natural killer cells.




Papers of note in Science Translational Medicine 9 (386)

2017-04-25T10:50:12-07:00

This week’s articles describe a new hydrogel that promotes chronic wound healing and a way to limit intestinal tissue damage from radiation, chemo, or hematopoietic cell transplant therapies.




Papers of note in Science 356 (6335)

2017-04-25T10:50:12-07:00

This week’s articles highlight a peptide that controls myoblast fusion; a metabolic adaptation that enables naked mole-rats to resist the detrimental effects of anoxia; a transcription factor that coordinates signaling in the mammary epithelial stem cell niche; and transgenerational epigenetic inheritance of the response to an environmental stimulus.




Blocking a signal to host cell histones

2017-04-25T10:50:12-07:00

A plant pathogen suppresses the host immune response by preventing histone acetylation.




Discovering relationships between nuclear receptor signaling pathways, genes, and tissues in Transcriptomine

2017-04-25T10:50:12-07:00

We previously developed a web tool, Transcriptomine, to explore expression profiling data sets involving small-molecule or genetic manipulations of nuclear receptor signaling pathways. We describe advances in biocuration, query interface design, and data visualization that enhance the discovery of uncharacterized biology in these pathways using this tool. Transcriptomine currently contains about 45 million data points encompassing more than 2000 experiments in a reference library of nearly 550 data sets retrieved from public archives and systematically curated. To make the underlying data points more accessible to bench biologists, we classified experimental small molecules and gene manipulations into signaling pathways and experimental tissues and cell lines into physiological systems and organs. Incorporation of these mappings into Transcriptomine enables the user to readily evaluate tissue-specific regulation of gene expression by nuclear receptor signaling pathways. Data points from animal and cell model experiments and from clinical data sets elucidate the roles of nuclear receptor pathways in gene expression events accompanying various normal and pathological cellular processes. In addition, data sets targeting non-nuclear receptor signaling pathways highlight transcriptional cross-talk between nuclear receptors and other signaling pathways. We demonstrate with specific examples how data points that exist in isolation in individual data sets validate each other when connected and made accessible to the user in a single interface. In summary, Transcriptomine allows bench biologists to routinely develop research hypotheses, validate experimental data, or model relationships between signaling pathways, genes, and tissues.




p53 dynamics in response to DNA damage vary across cell lines and are shaped by efficiency of DNA repair and activity of the kinase ATM

2017-04-25T10:50:12-07:00

Cellular systems show a wide range of signaling dynamics. Many of these dynamics are highly stereotyped, such as oscillations at a fixed frequency. However, most studies looking at the role of signaling dynamics focus on one or a few cell lines, leaving the diversity of dynamics across tissues or cell lines a largely unexplored question. We focused on the dynamics of the tumor suppressor protein p53, which regulates cell cycle arrest and apoptosis in response to DNA damage. We established live-cell reporters for 12 cancer cell lines expressing wild-type p53 and quantified p53 dynamics in response to double-strand break–inducing DNA damage. In many of the tested cell lines, we found that p53 abundance oscillated in response to ionizing radiation or the DNA-damaging chemotherapeutic neocarzinostatin and that the periodicity of the oscillations was fixed. In other cell lines, p53 abundance dynamically changed in different ways, such as a single broad pulse or a continuous induction. By combining single-cell assays of p53 signaling dynamics, small-molecule screening in live cells, and mathematical modeling, we identified molecules that perturbed p53 dynamics and determined that cell-specific variation in the efficiency of DNA repair and the activity of the kinase ATM (ataxia-telangiectasia mutated) controlled the signaling landscape of p53 dynamics. Because the dynamics of wild-type p53 varied substantially between cell lines, our study highlights the limitation of using one line as a model system and emphasizes the importance of studying the dynamics of other signaling pathways across different cell lines and genetic backgrounds.