Journal Article

A core viral protein binds host nucleosomes to sequester immune danger signals

Garcia, Benjamin A., Pancholi, Neha J., Herrmann, Christin, Ostapchuk, Philomena, Kulej, Katarzyna, Sekulic, Nikolina, Blumenthal, Daniel, Black, Ben E., Worthen, G. Scott, Petrescu, Joana, Avgousti, Daphne C., Weitzman, Matthew D., Seeholzer, Steven H., Paris, Andrew J., Hearing, Patrick, Molden, Rosalynn C., Reyes, Emigdio D.

2016

Overview

Here, a small core protein of human adenoviruses is shown to associate with histones, sequestering proteins on host chromatin and preventing inflammatory proteins from being released and triggering inflammation. A viral protein that targets nucleosomes Matthew Weitzman and colleagues reveal a previously unknown method by which a virus can subvert the host inflammatory response. They show that a small core protein of human adenoviruses associates with histones and can alter the sequestration of proteins on host chromatin. Specifically, adenovirus protein VII forms complexes with nucleosomes and leads to the retention of the inflammatory protein HMGB1 on chromatin, preventing it from being released and triggering inflammation. Viral proteins mimic host protein structure and function to redirect cellular processes and subvert innate defenses 1 . Small basic proteins compact and regulate both viral and cellular DNA genomes. Nucleosomes are the repeating units of cellular chromatin and play an important part in innate immune responses 2 . Viral-encoded core basic proteins compact viral genomes, but their impact on host chromatin structure and function remains unexplored. Adenoviruses encode a highly basic protein called protein VII that resembles cellular histones 3 . Although protein VII binds viral DNA and is incorporated with viral genomes into virus particles 4 , 5 , it is unknown whether protein VII affects cellular chromatin. Here we show that protein VII alters cellular chromatin, leading us to hypothesize that this has an impact on antiviral responses during adenovirus infection in human cells. We find that protein VII forms complexes with nucleosomes and limits DNA accessibility. We identified post-translational modifications on protein VII that are responsible for chromatin localization. Furthermore, proteomic analysis demonstrated that protein VII is sufficient to alter the protein composition of host chromatin. We found that protein VII is necessary and sufficient for retention in the chromatin of members of the high-mobility-group protein B family (HMGB1, HMGB2 and HMGB3). HMGB1 is actively released in response to inflammatory stimuli and functions as a danger signal to activate immune responses 6 , 7 . We showed that protein VII can directly bind HMGB1 in vitro and further demonstrated that protein VII expression in mouse lungs is sufficient to decrease inflammation-induced HMGB1 content and neutrophil recruitment in the bronchoalveolar lavage fluid. Together, our in vitro and in vivo results show that protein VII sequesters HMGB1 and can prevent its release. This study uncovers a viral strategy in which nucleosome binding is exploited to control extracellular immune signalling.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 14 / 14/1 / 14/19 / 14/34 / 14/35 / 631/250/262 / 631/326/596/1278 / 631/337/100/1701 / 82 / 82/58 / 82/83 / Adenoviridae - chemistry / Adenoviruses / Alarmins - metabolism / Animals / Bronchoalveolar Lavage Fluid - cytology / Bronchoalveolar Lavage Fluid - immunology / Cell Line / Chromatin Assembly and Disassembly - drug effects / Deoxyribonucleic acid / DNA / Genomes / Health aspects / Histones - metabolism / HMGB1 Protein - metabolism / HMGB1 Protein - secretion / Host-virus relationships / Humanities and Social Sciences / Humans / Immune response / Immunity, Innate - drug effects / Immunology / Infections / Inflammation - immunology / Inflammation - metabolism / letter / Lung - immunology / Lung - metabolism / Male / Mice / multidisciplinary / Neutrophil Infiltration - drug effects / Neutrophil Infiltration - immunology / Nucleosomes - chemistry / Nucleosomes - drug effects / Nucleosomes - genetics / Nucleosomes - metabolism / Observations / Protein Binding / Protein Processing, Post-Translational / Proteins / Proteomics / Science / Signal transduction / Studies / Viral Core Proteins - chemistry / Viral Core Proteins - metabolism / Viral Core Proteins - pharmacology / Viral proteins