Proteolethargy is a pathogenic mechanism in chronic disease

The pathogenic mechanisms of many diseases are well understood at the molecular level, but there are prevalent syndromes associated with pathogenic signaling, such as diabetes and chronic inflammation, where our understanding is more limited. Here we report that pathogenic signaling suppresses the mobility of a spectrum of proteins that play essential roles in cellular functions known to be dysregulated in these chronic diseases. The reduced protein mobility, which we call proteolethargy, was linked to cysteine residues in the affected proteins and signaling-related increases in excess reactive oxygen species. Diverse pathogenic stimuli, including hyperglycemia, dyslipidemia and inflammation, produce similar reduced protein mobility phenotypes. We propose that proteolethargy is an overlooked cellular mechanism that may account for various pathogenic features of diverse chronic diseases. To investigate the role of pathogenic signaling on transcriptional regulation and heterochromatic repression, we treated HepG2 cells with 3 nM insulin (insulin resistant samples) or 0.1 nM insulin (insulin sensitive samples) as a control for 3 days. We next performed differential gene analysis using data obtained from RNA-seq of 3 replicates each for resistant samples and sensitive samples.