Kumar Anita V, Kang Taewook, Thakurta Tara G, Ng Celeste, Rogers Aric N, Larsen Martin R, Lapierre Louis R
Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, 185 Meeting St., Providence, RI 02912, USA.
Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark.
Sci Adv. 2022 Apr;8(13):eabj1604. doi: 10.1126/sciadv.abj1604. Epub 2022 Apr 1.
Altered nucleolar and ribosomal dynamics are key hallmarks of aging, but their regulation remains unclear. Building on the knowledge that the conserved nuclear export receptor Exportin 1 (XPO-1/XPO1) modulates proteostasis and life span, we systematically analyzed the impact of nuclear export on protein metabolism. Using transcriptomic and subcellular proteomic analyses in nematodes, we demonstrate that XPO-1 modulates the nucleocytoplasmic distribution of key proteins involved in nucleolar dynamics and ribosome function, including fibrillarin (FIB-1/FBL) and RPL-11 (RPL11). Silencing led to marked reduction in global translation, which was accompanied by decreased nucleolar size and lower fibrillarin levels. A targeted screen of known proteostatic mediators revealed that the autophagy protein LGG-1/GABARAP modulates nucleolar size by regulating RPL-11 levels, linking specific protein degradation to ribosome metabolism. Together, our study reveals that nucleolar size and life span are regulated by LGG-1/GABARAP via ribosome protein surveillance.
核仁及核糖体动力学的改变是衰老的关键标志，但其调控机制仍不清楚。基于保守的核输出受体输出蛋白1（XPO-1/XPO1）调节蛋白质稳态和寿命这一知识，我们系统地分析了核输出对蛋白质代谢的影响。通过对线虫进行转录组和亚细胞蛋白质组分析，我们证明XPO-1调节参与核仁动力学和核糖体功能的关键蛋白的核质分布，包括纤维蛋白原（FIB-1/FBL）和核糖体蛋白L-11（RPL-11）。基因沉默导致整体翻译显著减少，同时核仁大小减小且纤维蛋白原水平降低。对已知蛋白质稳态调节因子的靶向筛选表明，自噬蛋白LGG-1/GABARAP通过调节RPL-11水平来调节核仁大小，将特定的蛋白质降解与核糖体代谢联系起来。总之，我们的研究表明，LGG-1/GABARAP通过核糖体蛋白监测来调节核仁大小和寿命。
