ABSTRACT
Ribosome biogenesis is essential for protein synthesis, cell growth and survival. The process takes places in nucleoli and is orchestrated by various proteins, among them RNA polymerases I-III as well as ribosome biogenesis factors. Perturbation of ribosome biogenesis activates the nucleolar stress response, which classically triggers cell cycle arrest and apoptosis. Nucleolar stress is utilized in modern anti-cancer therapies, however, also contributes to the development of various pathologies, including cancer. Growing evidence suggests that nucleolar stress stimulates compensatory cascades, for instance bulk autophagy. However, underlying mechanisms are poorly understood. Here we demonstrate that induction of nucleolar stress activates expression of key autophagic regulators such as ATG7 and ATG16L1, essential for generation of autophagosomes. We show that knockdown of the ribosomopathy factor SBDS, or of key ribosome biogenesis factors (PPAN, NPM, PES1) is associated with enhanced levels of ATG7 in cancer cells. The same holds true when interfering with RNA polymerase I function by either pharmacological inhibition (CX-5461) or depletion of the transcription factor UBF-1. Moreover, we demonstrate that RNA pol I inhibition by CX-5461 stimulates autophagic flux. Together, our data establish that nucleolar stress affects transcriptional regulation of autophagy. Given the contribution of both axes in propagation or cure of cancer, our data uncover a connection that might be targeted in future.
ABSTRACT
Alzheimer's disease (AD) and cataract represent two common protein misfolding diseases closely associated with aging. Growing evidence suggests that these two diseases may be interrelated with each other through cross-sequence interactions between ß-amyloid (Aß) peptide and the short aggregating peptides derived from proteolytic breakdown of α-crystallin. αΑ(66-80) is one of several peptides produced by the proteolytic breakdown of α-crystallin in aged eye lens. Although it is evident that the Aß(1-40) and αΑ(66-80) coexist in aged eye lenses and both the peptides are known to form macromolecular assemblies, their cross-sequence interaction and the seeding behavior are not known. In this study, the aggregation behavior of αΑ(66-80) has been examined in the presence of Aß(1-40) on using thioflavin T (ThT) based aggregation kinetics. The presence of monomeric Aß(1-40) augmented the aggregation kinetics of αΑ(66-80) and reduced the lag time of αΑ(66-80) aggregation. However, the addition of Aß(1-40) or αΑ(66-80) fibrils (seeds) didn't result in any change in the rate of αΑ(66-80) aggregation. In this in vitro study, we could show that the presence Aß(1-40) has substantial effect on the aggregation of αΑ(66-80), which suggests a possible interaction between AD and cataract pathologies.
