title: A core viral protein binds host nucleosomes to sequester immune danger signals.
abstract: Viral proteins mimic host protein structure and function to redirect cellular processes and subvert innate defenses. 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. 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. Although protein VII binds viral DNA and is incorporated with viral genomes into virus particles, 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. 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 signaling.
authors.forename: Daphne C
authors.initials: DC
authors.lastname: Avgousti
authors.forename: Christin
authors.initials: C
authors.lastname: Herrmann
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kulej
authors.forename: Neha J
authors.initials: NJ
authors.lastname: Pancholi
authors.forename: Nikolina
authors.initials: N
authors.lastname: Sekulic
authors.forename: Joana
authors.initials: J
authors.lastname: Petrescu
authors.forename: Rosalynn C
authors.initials: RC
authors.lastname: Molden
authors.forename: Daniel
authors.initials: D
authors.lastname: Blumenthal
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Paris
authors.forename: Emigdio D
authors.initials: ED
authors.lastname: Reyes
authors.forename: Philomena
authors.initials: P
authors.lastname: Ostapchuk
authors.forename: Patrick
authors.initials: P
authors.lastname: Hearing
authors.forename: Steven H
authors.initials: SH
authors.lastname: Seeholzer
authors.forename: G Scott
authors.initials: GS
authors.lastname: Worthen
authors.forename: Ben E
authors.initials: BE
authors.lastname: Black
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Garcia
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Weitzman
mesh_terms: D000256:Adenoviridae / Q000737:chemistry*; D000067531:Alarmins / Q000378:metabolism; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D002460:Cell Line; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects; D024243:HMGB1 Protein / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000276:immunology; D009707:Nucleosomes / Q000737:chemistry / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D040901:Proteomics; D014758:Viral Core Proteins / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D000067531:Alarmins; D024243:HMGB1 Protein; D006657:Histones; D009707:Nucleosomes; D014758:Viral Core Proteins