秀丽隐杆线虫
磷酸化
生物
原癌基因蛋白质c-akt
长寿
激酶
胰岛素受体
酪蛋白激酶1
细胞生物学
突变体
信号转导
酪蛋白激酶2
转录因子
蛋白激酶B
遗传学
胰岛素
蛋白激酶A
基因
丝裂原活化蛋白激酶激酶
内分泌学
胰岛素抵抗
作者
Wen-Jun Li,Chenwei Wang,Tao Li,Yong Yan,Mei Jun Zhang,Zexian Liu,Yu-Xin Li,Han Zhao,Xue Mei Li,Xian-Dong He,Yu Xue,Meng‐Qiu Dong
标识
DOI:10.1038/s41467-021-24816-z
摘要
Abstract Insulin/IGF-1 Signaling (IIS) is known to constrain longevity by inhibiting the transcription factor FOXO. How phosphorylation mediated by IIS kinases regulates lifespan beyond FOXO remains unclear. Here, we profile IIS-dependent phosphorylation changes in a large-scale quantitative phosphoproteomic analysis of wild-type and three IIS mutant Caenorhabditis elegans strains. We quantify more than 15,000 phosphosites and find that 476 of these are differentially phosphorylated in the long-lived daf-2/insulin receptor mutant. We develop a machine learning-based method to prioritize 25 potential lifespan-related phosphosites. We perform validations to show that AKT-1 pT492 inhibits DAF-16/FOXO and compensates the loss of daf-2 function, that EIF-2α pS49 potently inhibits protein synthesis and daf-2 longevity, and that reduced phosphorylation of multiple germline proteins apparently transmits reduced DAF-2 signaling to the soma. In addition, an analysis of kinases with enriched substrates detects that casein kinase 2 (CK2) subunits negatively regulate lifespan. Our study reveals detailed functional insights into longevity.
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