Ohigashi Noritaka, Hirayama Shoshiro, Yashiroda Hideki, Murata Shigeo
Laboratory of Protein Metabolism, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
Department of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Teikyo Heisei University, Tokyo, Japan.
Genes Cells. 2025 Mar;30(2):e70004. doi: 10.1111/gtc.70004.
The proteasome is a large multicatalytic complex conserved across eukaryotes that regulates multiple cellular processes through the degradation of ubiquitinated proteins. The proteasome is predominantly localized to the nucleus in proliferating cells and translocates to the cytoplasm in the stationary phase. Sts1 reportedly plays a vital role in the nuclear import of the proteasome during proliferation in yeast Saccharomyces cerevisiae. However, the mechanisms underlying cytoplasmic translocation of the proteasome in the stationary phase remain unknown. Here, we showed that the ubiquitin ligase Hul5 promotes vacuolar sequestration of Sts1 in a catalytic activity-dependent manner and thus suppresses the nuclear import of the proteasome during the stationary phase. We further demonstrated that cytoplasmic translocation of the proteasome plays a vital role in the clearance of ubiquitinated protein aggregates, mitochondrial quality control, and resuming proliferation from cellular quiescence. Our results provide insights into the mechanisms and significance of the cytoplasmic localization of proteasomes in cellular quiescence.
蛋白酶体是一种在真核生物中保守的大型多催化复合体，它通过降解泛素化蛋白来调节多种细胞过程。在增殖细胞中，蛋白酶体主要定位于细胞核，而在静止期则转移至细胞质。据报道，在酿酒酵母增殖过程中，Sts1在蛋白酶体的核输入中起着至关重要的作用。然而，蛋白酶体在静止期细胞质转移的潜在机制仍不清楚。在此，我们表明泛素连接酶Hul5以催化活性依赖的方式促进Sts1的液泡隔离，从而在静止期抑制蛋白酶体的核输入。我们进一步证明，蛋白酶体的细胞质转移在泛素化蛋白聚集体的清除、线粒体质量控制以及从细胞静止状态恢复增殖中起着至关重要的作用。我们的研究结果为细胞静止期蛋白酶体细胞质定位的机制和意义提供了见解。
