ArticlePLoS biology2026
The histone methyltransferase complex subunit RBBP5 serves as a central epigenetic regulator of proteostasis dynamics.
Article in PLoS biology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
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.
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