Adenovirus E1B-55K controls SUMO-dependent degradation of antiviral cellular restriction factors

Wing-Hang Ip, Michael H. Tatham, Steewen Krohne, Julia Gruhne, Michael Melling, Tina Meyer, Britta Gornott, Luca D. Bertzbach, Ronald T. Hay, Estefania Rodriguez, Thomas Dobner (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)
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Abstract

The human adenovirus species C type 5 (HAdV-C5) early region 1B 55 kDa (E1B-55K) protein is a multifunctional protein that promotes viral replication and adenovirus-mediated cell transformation through various mechanisms that primarily counteract host intrinsic and innate immunity. These include post-translational activities that exploit the host cell ubiquitin and small ubiquitin-like modifier (SUMO) conjugation machineries to regulate antiviral cellular restriction factors. However, despite significant advancements in this field, several underlying mechanisms governing these processes remain unidentified to date. Here, we performed stable isotope labeling by amino acids in cell culture (SILAC)-based quantitative SUMO proteomics to better understand cellular consequences of E1B-55K-mediated host cell modulation and adenovirus infection in general. We assessed cellular proteins for abundance changes and SUMO2 conjugate proteome changes during infection with wild-type HAdV-C5 or an E1B-55K deletion mutant. We provide evidence that changes in the SUMOylated proteome have the potential to regulate the DNA damage response, cell cycle control, chromatin assembly, and gene transcription and present these data as a resource for the research community. Strikingly, we identified a SUMO-dependent, ubiquitin-mediated degradation mechanism for some SUMO substrates, suggesting that E1B-55K may use multiple mechanisms to alter the activity of restrictive cellular pathways.IMPORTANCEHuman adenoviruses (HAdVs) generally cause mild and self-limiting diseases of the upper respiratory and gastrointestinal tracts but pose a serious risk to immunocompromised patients and children. Moreover, they are widely used as vectors for vaccines and vector-based gene therapy approaches. It is therefore vital to thoroughly characterize HAdV gene products and especially HAdV virulence factors. Early region 1B 55 kDa protein (E1B-55K) is a multifunctional HAdV-encoded oncoprotein involved in various viral and cellular pathways that promote viral replication and cell transformation. We analyzed the E1B-55K dependency of SUMOylation, a post-translational protein modification, in infected cells using quantitative proteomics. We found that HAdV increases overall cellular SUMOylation and that this increased SUMOylation can target antiviral cellular pathways that impact HAdV replication. Moreover, we showed that E1B-55K orchestrates the SUMO-dependent degradation of certain cellular antiviral factors. These results once more emphasize the key role of E1B-55K in the regulation of viral and cellular proteins in productive HAdV infections.

Original languageEnglish
Article numbere0079123
Number of pages21
JournalJournal of Virology
Volume97
Issue number11
Early online date2 Nov 2023
DOIs
Publication statusPublished - 30 Nov 2023

Keywords

  • DNA damage response
  • E1B-55K
  • SUMO E3-ligase
  • SUMO proteomics
  • cell cycle regulation
  • chromatin assembly
  • post-translational modification (PTM)
  • protein network analysis
  • small ubiquitin-like modifier (SUMO)
  • viral transcription

ASJC Scopus subject areas

  • Insect Science
  • Virology
  • Microbiology
  • Immunology

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