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Monitoring SUMO-2 proteome changes during adenovirus infection using WT and an E1B-55k mutant.

ABSTRACT: The human adenovirus type 5 (HAdV-C5) early region 1B 55-kDa protein (E1B-55K) 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 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 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 E1B-55K deletion mutants. 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. 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.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell

DISEASE(S): Cervix Carcinoma

SUBMITTER: Mike Tatham

LAB HEAD: Ronald Thomas

PROVIDER: PXD042236 | Pride | 2023-10-17

REPOSITORIES: Pride

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Project description:To combat virus infections, which are major human killers, a deeper understanding of how viruses reprogram their hosts to create optimal production of progeny is needed. Most knowledge on the regulation of cellular gene expression during adenovirus infection is derived from studies of mRNA expression. Here, we investigated the changes in cellular protein expression during the late phase of adenovirus type 2 (Ad2) infection of primary human cells by stable isotope labeling in cell culture (SILAC) with subsequent liquid chromatography-high resolution tandem mass spectrometric (LC-MS/MS) analysis using a Q-Exactive Orbitrap instrument. Cells were in-depth evaluated 24 and 36 hours post infection (hpi) and two biological replicates were investigated using swapped labeling. In total, 2648 and 2394 proteins were quantified at 24 and 36 hpi, respectively. Among them, 659 and 645 were deregulated more than 1.6-fold at the two time points, and approximately 80% of them had sustained regulation from 24 to 36 hpi. For the deregulated genes the change in protein expression was compared with that of RNA expression using cDNA sequencing data from the same time points of infection. The comparison revealed a surprisingly low correlation (r = 0.3). Consistency between changes in RNA and protein expression was observed for approximately 30% of the genes, whereas a majority showed either divergent or opposite expression profiles. The deregulated proteins were subjected to pathway and biological function analysis using bioinformatics tools. A surprising observation was that proteins related to carbohydrate metabolism were up-regulated at the protein level but unchanged at the RNA level whereas histone proteins were down-regulated at the protein level but up-regulated at the RNA level. Our results show that regulation of cellular gene expression in the response to viral infection is more complex than hitherto believed and several examples of posttranscriptional regulation of gene expression were observed. The results contribute to our understanding of host cell gene regulation during infection at a deeper level.

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Monitoring SUMO-2 proteome changes during adenovirus infection using WT and an E1B-55k mutant.

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