Biology subjects

Itakura, E.

Publications and source records attributed to Itakura, E..

3 recordsLinked to original sources

bioRxiv2024

Regulatory Dynamics of Sch9 in Response to Cytosolic Acidification: From Spatial Reconfiguration to Cellular Adaptation to Stresses

The regulation of cellular metabolism in response to intracellular and extracellular conditions is critical for cell survival. In Saccharomyces cerevisiae, Sch9 is a well-established substrate of the target of rapamycin complex 1 (TORC1) and regulates metabolic pathways and stress responses. Sch9 is enriched on the vacuolar membrane through binding to PI(3,5)P2, and this localization is essential for TORC1-dependent phosphorylation. Previous studies have demonstrated that glucose starvation and oxidative stress cause the dissociation of Sch9 from the vacuolar membrane. However, the underlying mechanism and physiological significance of the change in Sch9 localization still require elucidation. In this study, we demonstrated that cytosolic pH is a regulator of Sch9 localization. We observed that multiple stress conditions that induce cytosolic acidification consistently led to the detachment of Sch9 from the vacuolar membrane. Furthermore, we confirmed that the affinity between Sch9 and PI(3,5)P2 is pH-dependent in vitro. This pH-dependent localization switch of Sch9 is linked to selective regulation of the TORC1-Sch9 pathway. Impairment of the dissociation of Sch9 from the vacuolar membrane in response to cytosolic acidification resulted in deficient induction of the expression of the stress response gene and delayed the adaptive response to acetic acid stress. These findings indicate that the appropriate control of Sch9 localization is essential for metabolic reprogramming.

cell biology↗

bioRxiv2023

Identification of novel autophagy inducers by accelerating lysosomal clustering against Parkinson's disease

Autophagy-lysosome pathway plays an indispensable role in the intracellular protein quality control system, degrading abnormal organelles and proteins. Among these proteins is -Synuclein (Syn), which is associated with the pathogenesis of Parkinsons disease (PD). However, the activation of this lysosome-dependent degradation strategy is restricted by enzyme complementation. In this study, we focused on the phase of autophagosome-lysosome fusion around the microtubule organizing center (MTOC) that leads to Syn degradation. Through high-throughput chemical screening, we identified six clinically available drugs that enhance autophagy and can accumulate lysosomes around the MTOC from approximately 1,200 drugs screened. We further demonstrated that these compounds induce lysosomal clustering through a JIP4-TRPML1-dependent mechanism, which is associated with autophagy induction. Among these, the lysosomal clustering compound albendazole was observed to promote the autophagy-dependent degradation of Triton-X-insoluble proteasome inhibitor-induced aggregates (p62). In a cellular PD model, albendazole boosted the degradation of insoluble Syn, an effect that was reversed upon the addition of bafilomycin A1. Our results suggest that lysosomal clustering can facilitate the breakdown of protein aggregates. Therefore, compounds that promote lysosomal clustering may offer a promising therapeutic strategy against neurodegenerative diseases characterized by the presence of aggregate-prone proteins.

cell biology↗

bioRxiv2023

Fluctuation of lysosomal protein degradation in neural stem cells of postnatal mouse brain

Lysosomes are intracellular organelles responsible for degrading diverse macromolecules delivered from several pathways, such as the endo-lysosomal and autophagic pathways. Recent reports have suggested that lysosomes are essential in regulating neural stem cells in developing, adult, and aged brains. However, the activity of these lysosomes has not yet been monitored in these brain tissues. Here, we report a new probe to measure lysosomal protein degradation in brain tissue by immunostaining. Our results demonstrate the fluctuation of lysosomal protein degradation in neural stem cells depending on age and brain disorder. Neural stem cells increase lysosomal activity during hippocampal development in the dentate gyrus, but aging and aging-related disease reduces their activity. In addition, physical exercise increases lysosomal activity in neural stem cells and astrocytes. We hypothesize three different stages of lysosomal activity: the increase in development, the stable state for the adult stage, and the reduction by damages with age or disease.

neuroscience↗