Multi-omic data integration links Deleted in Breast Cancer 1 (DBC1) Degradation to Chromatin Remodeling in Inflammatory Response

Journal Article · Mon Aug 12 00:00:00 EDT 2013 · Molecular & Cellular Proteomics. MCP, 12(8):2136-2147

DOI:https://doi.org/10.1074/mcp.M112.026138· OSTI ID:1094931

Nakayasu, Ernesto S.; Brown, Roslyn N.; Ansong, Charles; Sydor, Michael A.; Imtiaz, Sayed; Mihai, Cosmin; Sontag, Ryan L.; Hixson, Kim K.; Monroe, Matthew E.; Sobreira, Tiago; Orr, Galya; Petyuk, Vladislav A.; Yang, Feng; Smith, Richard D.; Adkins, Joshua N.

Ubiquitination is a common protein post-translational modification that regulates many key cellular functions. Here we investigated the dynamics of ubiquitinated proteins after an inflammatory stimulation of RAW264.7 macrophage-like cells with bacterial lipopolysaccharide. We demonstrate that levels of global ubiquitination, and K48 and K63 polyubiquitination change after lipopolysaccharide stimulation. A quantitative proteomic analysis identified 1199 ubiquitinated proteins, 78 of which had significantly changed ubiquitination levels after lipopolysaccharide stimulation. We next identified a subset of proteins that were targeted for degradation after lipopolysaccharide stimulation, by integrating the ubiquitinome data with global proteomics and transcriptomics results. Using cellular assays and western blot analyses we biochemically validated DBC1, a histone deacetylase inhibitor not previously linked to inflammation, as a degradation substrate, which is targeted via an orchestrated mechanism utilizing caspases and the proteasome. The degradation of DBC1 releases histone deacetylase activity, linking lipopolysaccharide activation to chromatin remodeling in caspase- and proteasome-mediated signaling.

• Research Organization: Pacific Northwest National Lab. (PNNL), Richland, WA (United States). Environmental Molecular Sciences Lab. (EMSL)
• Sponsoring Organization: USDOE
• DOE Contract Number: AC05-76RL01830
• OSTI ID: 1094931
• Report Number(s): PNNL-SA-88392; 39976; 47622; 42294; 400412000
• Journal Information: Molecular & Cellular Proteomics. MCP, 12(8):2136-2147, Journal Name: Molecular & Cellular Proteomics. MCP, 12(8):2136-2147
• Country of Publication: United States
• Language: English

Related Subjects

Environmental Molecular Sciences Laboratory