Preservation of orphan ribosomal proteins during stress in chaperone-stirred condensates

Ribosome biogenesis is among the most resource-intensive cellular processes, with ribosomal proteins accounting for up to half of all newly synthesized proteins in eukaryotic cells. During stress, cells shut down ribosome biogenesis in part by halting rRNA synthesis, potentially leading to massive accumulation of aggregation-prone “orphan” ribosomal proteins (oRPs). Here we show that during heat shock in yeast and human cells, oRPs accumulate as reversible condensates at the nucleolar periphery recognized by the Hsp70 co-chaperone Sis1/DnaJB6. oRP condensates are liquid-like in cell-free lysate but solidify upon depletion of Sis1 or inhibition of Hsp70. When cells recover from heat shock, oRP condensates disperse in a Sis1-dependent manner, and their ribosomal protein constituents are incorporated into functional ribosomes in the cytosol, enabling cells to efficiently resume growth.核糖体生物发生（Ribosome biogenesis）是细胞中资源消耗最为庞大的生理过程之一，核糖体蛋白占真核细胞新合成蛋白质总量的一半之多。当细胞遭遇应激时，会通过阻断核糖体RNA（rRNA）合成的方式部分抑制核糖体生物发生，这可能引发大量易聚集的“孤儿”核糖体蛋白（orphan ribosomal proteins，下文简称oRPs）的蓄积。本研究表明，在酵母与人类细胞的热激过程中，oRPs会以可逆凝聚体的形式聚集在核仁周边区域，并可被热休克蛋白70（Hsp70）的辅助分子伴侣（co-chaperone）Sis1/DnaJB6识别。在无细胞裂解液（cell-free lysate）中，oRP凝聚体呈类液态；但当Sis1耗尽或Hsp70活性被抑制时，凝聚体将发生固化。当细胞从热激中恢复时，oRP凝聚体以Sis1依赖的方式解聚，其所含的核糖体蛋白组分可被整合到细胞质基质（cytosol）中的功能性核糖体中，使细胞能够高效恢复生长。