AI-facilitated multi-omics reveal TRF-controlled propionylation in determining protein homeostasis. Drosophila melanogaster

Temporal regulation of metabolic signals is essential for physiological adaptation to daily rhythm of nutrient availability and maintaining organismal health, but the mechanisms are not well understood. Here we characterized a new mechanism mediated by lysine propionylation (Kpr). We observed prominent circadian oscillation of Kpr in Drosophila heads, and proteomic profiling of 344 Kpr sites revealed that 23% of the propionylome exhibits temporal variation throughout the day. We developed a hybrid artificial intelligence (AI) framework to prioritize the propionylation at lysine 17 of H2B (H2BK17pr) to be functionally important. Both the circadian clock and feeding/fasting cycles regulate H2BK17pr oscillation, whereas temporal multi-omics profiling demonstrated that H2BK17pr likely regulates the rhythmic expression of proteasomal genes and protein metabolism in response to time-restricted feeding (TRF) during the active phase. Further experiments identified a potential role for H2BK17pr in modulating proteinstasis by promoting proteasome-mediated degradation, which may be conserved from fly to human.