AI Insight
Researchers identified RBBP5, a component of the COMPASS histone methyltransferase complex, as a critical epigenetic regulator controlling how cells maintain protein quality control (proteostasis). RBBP5 works with XBP1s to activate proteostasis genes by depositing H3K4me3 marks at their promoters and is essential for both the newly discovered 12-hour ultradian rhythm of proteostasis gene expression and cellular responses to protein-damaging stress. Loss of RBBP5 impairs autophagy and makes cells more vulnerable to proteotoxic stress, revealing how chromatin modifications dynamically coordinate protein quality control systems.
Why it matters
This discovery links epigenetic regulation to fundamental cellular protein maintenance systems that malfunction in aging, neurodegeneration, and metabolic diseases. Understanding RBBP5's role in proteostasis could inform therapeutic strategies for conditions like Alzheimer's disease, Parkinson's disease, and diabetes where protein quality control is compromised.
Understand the Science
by Syeda Kubra, Michelle Sun, William Dion, Yu Bian, Ahmet Catak, Hannah Luong, Haokun Wang, Yinghong Pan, Jia-Jun Liu, Aishwarya Ponna, Lijun Liu, Ian Sipula, Jian-Hua Luo, Michael J. Jurczak, Silvia Liu, Bokai Zhu
Proteostasis is essential for cellular health, with its disruption contributing to aging, neurodegeneration, and metabolic disorders. While the upstream proteotoxic stress-sensing and protein-folding mechanisms in the ER and cytosol are well studied, the transcriptional regulation of proteostasis remains incompletely understood, particularly concerning the temporal epigenome dynamics, chromatin landscapes, and co-regulatory networks underlying dynamic proteostasis control. Traditionally, proteotoxic stress responses were viewed as acute reactions to noxious stimuli, but recent evidence shows that many proteostasis genes exhibit ~12-hour ultradian rhythms under physiological conditions, driven by an XBP1s-dependent oscillator independent of the canonical circadian clock and cell cycle. By mapping the chromatin landscape of the murine 12-hour oscillator, we identified RBBP5—an essential subunit of the COMPASS complex responsible for H3K4 trimethylation—as a pivotal epigenetic regulator of proteostasis dynamics. In contrast, histone acetyltransferases and H3K9 acetylation were dispensable for dynamic proteostasis gene expression. RBBP5 is not only indispensable for the 12-hour oscillator but also essential for the transcriptional regulation of diverse proteotoxic stresses response, by coactivating XBP1s and promoting H3K4me3 deposition at the promoters of proteostasis genes. As a result, loss of RBBP5 sensitizes cells to proteotoxic stress in part due to impaired autophagy. Proximity labeling of H3K4me3 further uncovered a dynamic chromatin-associated proteomic architecture, including components of COMPASS, the Integrator complex and SWI/SNF remodelers, that constitutes the transcriptional response to proteotoxic stress. Together, these findings establish RBBP5 as a central regulator of proteostasis dynamics, essential for maintaining cellular resilience.