Decoding the functions of nuclear speckle in protein quality control

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

Investigators

Abstract

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 maintain 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 will not only deepen our understanding of proteostasis regulation but also unveil 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 diseases. We recently unveiled an unexpected role for nuclear speckles— membrane-less organelles traditionally viewed as facilitating mRNA processing and gene regulation, in proteostasis control. 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 five 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.