SPOC1-mediated antiviral host cell response is antagonized early in human adenovirus type 5 infection

PLoS Pathog. 2013;9(11):e1003775. doi: 10.1371/journal.ppat.1003775. Epub 2013 Nov 21.

Abstract

Little is known about immediate phases after viral infection and how an incoming viral genome complex counteracts host cell defenses, before the start of viral gene expression. Adenovirus (Ad) serves as an ideal model, since entry and onset of gene expression are rapid and highly efficient, and mechanisms used 24-48 hours post infection to counteract host antiviral and DNA repair factors (e.g. p53, Mre11, Daxx) are well studied. Here, we identify an even earlier host cell target for Ad, the chromatin-associated factor and epigenetic reader, SPOC1, recently found recruited to double strand breaks, and playing a role in DNA damage response. SPOC1 co-localized with viral replication centers in the host cell nucleus, interacted with Ad DNA, and repressed viral gene expression at the transcriptional level. We discovered that this SPOC1-mediated restriction imposed upon Ad growth is relieved by its functional association with the Ad major core protein pVII that enters with the viral genome, followed by E1B-55K/E4orf6-dependent proteasomal degradation of SPOC1. Mimicking removal of SPOC1 in the cell, knock down of this cellular restriction factor using RNAi techniques resulted in significantly increased Ad replication, including enhanced viral gene expression. However, depletion of SPOC1 also reduced the efficiency of E1B-55K transcriptional repression of cellular promoters, with possible implications for viral transformation. Intriguingly, not exclusive to Ad infection, other human pathogenic viruses (HSV-1, HSV-2, HIV-1, and HCV) also depleted SPOC1 in infected cells. Our findings provide a general model for how pathogenic human viruses antagonize intrinsic SPOC1-mediated antiviral responses in their host cells. A better understanding of viral entry and early restrictive functions in host cells should provide new perspectives for developing antiviral agents and therapies. Conversely, for Ad vectors used in gene therapy, counteracting mechanisms eradicating incoming viral DNA would increase Ad vector efficacy and safety for the patient.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae / genetics
  • Adenoviridae / metabolism*
  • Adenovirus E1B Proteins / genetics
  • Adenovirus E1B Proteins / metabolism
  • Adenovirus E4 Proteins / genetics
  • Adenovirus E4 Proteins / metabolism
  • Adenovirus Infections, Human / genetics
  • Adenovirus Infections, Human / metabolism*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • HEK293 Cells
  • Humans
  • Immunity, Innate*
  • Proteasome Endopeptidase Complex / genetics
  • Proteasome Endopeptidase Complex / metabolism
  • Proteolysis*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • Adenovirus E1B Proteins
  • Adenovirus E4 Proteins
  • DNA-Binding Proteins
  • E4orf6 protein, adenovirus
  • PHF13 protein, human
  • Transcription Factors
  • Proteasome Endopeptidase Complex

Grant support

The Heinrich Pette Institute, Leibniz Institute for Experimental Virology is supported by the Freie und Hansestadt Hamburg and the Bundesministerium für Gesundheit (BMG). SS is supported by grants from the Peter und Traudl Engelhorn-Stiftung, the Erich und Gertrud Roggenbuck-Stiftung and the B. Braun-Stiftung. TD is supported by the Wilhelm Sander-Stiftung and the Deutsche Forschungsgemeinschaft. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.