73 3 Responses of alveolar-like macrophages to lysine deacetylase inhibition enrichment analysis and protein interaction network building (Figure 4A) (43). The most significant cluster identified after MS275+LPS treatment compared to LPS treatment alone was “Protein processing in endoplasmic reticulum” which also encompasses “Modification-dependent macromolecule catabolic process” and “cellular macromolecule catabolic process”. This cluster mainly comprised proteins that take part in the ubiquitination of other proteins. The second most significant cluster found was “Biosynthesis of amino acids”, which also includes “alpha-amino acid biosynthetic process” and “2-oxocarboxylic acid metabolism” pathways. These pathways comprise the mechanisms necessary to synthesize amino acids, including glycolysis, the TCA cycle, and the pentose phosphate pathway. Other relevant clusters were the “fructose 6-metabolic process” and the “tricarboxylic acid (TCA) cycle and respiratory electron transport”. These pathways collectively include the major metabolic pathways that are involved in macrophage polarization and that provide energy to cells. We only found 7 up- and 13 downregulated proteins in cells treated with RGFP966+LPS compared to LPS (reported in the supplementary data, Supplementary Table 2). Pathway enrichment analysis and protein interaction network building (Figure 4B) once again showed that the most significant cluster “Ub-specific processing proteases”, was related to the ubiquitination and deubiquitination of proteins. The cluster “RNA polymerase II transcription regulator complex” was the second most significantly enriched pathway. This cluster encompasses proteins that regulate transcription by RNA polymerase II, a process that is regulated by a number of mechanisms, including alterations of chromatin structure (44), and therefore it is not surprising that inhibition of lysine deacetylation leads to changes in proteins belonging to this pathway.
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