Exportin 1 modulates life span by regulating nucleolar dynamics via the autophagy protein LGG-1/GABARAP
Exportin 1 modulates life span by regulating nucleolar dynamics via the autophagy protein LGG-1/GABARAP
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DOI：
10.1126/sciadv.abj1604
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发表时间：
2022-04-01
期刊：
影响因子：
13.6
通讯作者：
Lapierre, Louis R.
中科院分区：
文献类型：
--
作者：
Kumar, Anita, V;Kang, Taewook;Lapierre, Louis R.
核仁和核糖体动力学的改变是衰老的关键标志，但其调节机制仍不清楚。基于保守的核输出受体 Exportin 1 (XPO-1/XPO1) 调节蛋白质稳态和寿命的知识，我们系统地分析了核输出对蛋白质代谢的影响。通过在线虫的转录组学和亚细胞蛋白质组学分析，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质的核质分布，包括纤维蛋白 (FIB-1/FBL) 和 RPL-11 (RPL11)。沉默 xpo-1 会导致整体翻译显着减少，同时伴随着核仁大小的减小和原纤维蛋白水平的降低。对已知蛋白抑制介质的针对性筛选表明，自噬蛋白 LGG-1/GABARAP 通过调节 RPL-11 水平来调节核仁大小，将特定蛋白降解与核糖体代谢联系起来。总之，我们的研究表明，核仁大小和寿命是由 LGG-1/GABARAP 通过核糖体蛋白监测来调节的。
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 xpo-1 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.