Sorbate Induces Lysine Sorbylation Through Non-Canonical Activities of Class I HDACs to Regulate the Expression of Inflammation Genes

Metabolic and environmental factors may impact gene expression through the production of active metabolites and epigenetic modifications of histones and transcription factors. In this study, we discovered that cellular uptake of sorbate, an FDA-approved and widely used food preservative, can induce lysine sorbylation (Ksor), a new posttranslational modification and epigenetic mark. We identified over 40 Ksor sites on core histones from mammalian cells and tissue upon sorbate uptake and further showed that the dynamics of histone Ksor could be regulated by the non-canonical activities of Class I histone deacetylases (HDAC1-3). We demonstrated that Class I HDACs catalyzed sorbylation upon sorbate uptake and desorbylation in the absence of sorbate both in vitro and in vivo. Sorbate uptake in mice livers led to a significant increase in histone Ksor without affecting overall histone acetylation, which correlated with the decreased expression of genes in inflammation signaling pathways. Accordingly, sorbate treatment in macrophage RAW264.7 cells upon LPS stimulation dose-dependently downregulated the expression of proinflammatory genes and production of nitric oxide. Global proteomic profiling revealed widespread lysine sorbylation substrates in diverse metabolic and signaling pathways and identified RelA (p65), a component of the NF-ĸB complex, and its interacting proteins as bona fide Ksor targets. Sorbate treatment significantly decreased NF-ĸB transcriptional activities in response to LPS stimulation in RAW264.7 cells. Taken together, our study demonstrated a non-canonical mechanism of sorbate uptake in regulating epigenetic histone modifications and inflammatory gene expression.