Folick Andrew, Oakley Holly D, Yu Yong, Armstrong Eric H, Kumari Manju, Sanor Lucas, Moore David D, Ortlund Eric A, Zechner Rudolf, Wang Meng C
Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA.
Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Science. 2015 Jan 2;347(6217):83-6. doi: 10.1126/science.1258857.
Lysosomes are crucial cellular organelles for human health that function in digestion and recycling of extracellular and intracellular macromolecules. We describe a signaling role for lysosomes that affects aging. In the worm Caenorhabditis elegans, the lysosomal acid lipase LIPL-4 triggered nuclear translocalization of a lysosomal lipid chaperone LBP-8, which promoted longevity by activating the nuclear hormone receptors NHR-49 and NHR-80. We used high-throughput metabolomic analysis to identify several lipids in which abundance was increased in worms constitutively overexpressing LIPL-4. Among them, oleoylethanolamide directly bound to LBP-8 and NHR-80 proteins, activated transcription of target genes of NHR-49 and NHR-80, and promoted longevity in C. elegans. These findings reveal a lysosome-to-nucleus signaling pathway that promotes longevity and suggest a function of lysosomes as signaling organelles in metazoans.
溶酶体是对人类健康至关重要的细胞器，其功能是消化和循环细胞外和细胞内的大分子。我们描述了溶酶体的一种影响衰老的信号传导作用。在秀丽隐杆线虫中，溶酶体酸性脂肪酶LIPL-4触发了溶酶体脂质伴侣LBP-8的核转位，LBP-8通过激活核激素受体NHR-49和NHR-80来促进长寿。我们使用高通量代谢组学分析来鉴定在组成型过表达LIPL-4的线虫中丰度增加的几种脂质。其中，油酰乙醇胺直接与LBP-8和NHR-80蛋白结合，激活NHR-49和NHR-80靶基因的转录，并促进秀丽隐杆线虫的长寿。这些发现揭示了一条促进长寿的溶酶体到细胞核的信号通路，并表明溶酶体在多细胞动物中作为信号细胞器的功能。
