Maintaining proper protein folding, trafficking, and turnover—collectively known as proteostasis—is crucial for cellular health. Disruptions in proteostasis, such as the accumulation of misfolded proteins, are implicated in various pathological conditions, including aging and neurodegeneration. To uphold proteome integrity, organisms employ a spectrum of protein quality control mechanisms, encompassing the ubiquitin-proteasome system (UPS), the ER-Golgi protein secretory pathways, ribosome quality control, and the autophagy-lysosomal pathway (ALP). While significant strides have been made in understanding these mechanisms individually, elucidating how they are coordinated across diverse cellular compartments both spatially and temporally remains a formidable challenge. Unraveling the mechanisms governing this spatiotemporal coordination is paramount. Identifying a central regulatory hub overseeing all protein quality control processes not only deepens our comprehension of proteostasis regulation but also unveils potential therapeutic targets. Targeting such a hub could simultaneously engage multiple quality control mechanisms, offering a more effective approach to addressing proteinopathies and aging-related ailments.
Recent findings have overturned the prevailing notion that protein quality control operates at a steady state under physiological conditions. Instead, we have discovered a 12-hour ultradian oscillator governing mammalian proteostasis gene expression independently of the 24-hour circadian clock and the cell cycle. This oscillator peaks at dawn and dusk, coinciding with heightened metabolic and proteostatic stress. Our investigations into this oscillator have unveiled an unexpected role for nuclear speckles—membrane-less organelles traditionally viewed as facilitating mRNA processing and gene regulation. Contrary to their previous characterization as simple "housekeeping" condensates, nuclear speckles emerge as pivotal sensors of proteostatic stress, orchestrating rapid stress responses by temporally coordinating the global transcriptional activation of proteostasis genes.
Over the next few years, our research aims to develop innovative tools to dissect how nuclear speckles detect proteostatic stress and regulate temporal proteostasis dynamics. Ultimately, we aspire to leverage this knowledge to devise novel therapeutic strategies for proteinopathies and aging-related diseases, with the goal of alleviating their burdens on human health.
