CELL
·
2024
·
IF 45.5
Zhi Zong,Feng Xie,Shuai Wang,Xiaojin Wu,Zhenyu Zhang,Bing Yang,Fangfang Zhou
Lysine lactylation is a post-translational modification that links cellular metabolism to protein function. Here, we find that AARS1 functions as a lactate sensor that mediates global lysine lacylation in tumor cells. AARS1 binds to lactate and catalyzes the formation of lactate-AMP, followed by transfer of lactate to the lysince acceptor residue. Proteomics studies reveal a large number of AARS1 targets, including p53 where lysine 120 and lysine 139 in the DNA binding domain are lactylated. Generation and utilization of p53 variants carrying constitutively lactylated lysine residues revealed that AARS1 lactylation of p53 hinders its liquid-liquid phase separation, DNA binding, and transcriptional activation. AARS1 expression and p53 lacylation correlate with poor prognosis among cancer patients carrying wild type p53. β-alanine disrupts lactate binding to AARS1, reduces p53 lacylation, and mitigates tumorigenesis in animal models. We propose that AARS1 contributes to tumorigenesis by coupling tumor cell metabolism to proteome alteration.
研究领域:
癌症生物学
·
分子生物学
·
细胞代谢
·
蛋白质组学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Metabolism
·
2026
·
IF 37
Yiming Wang,Fan Li,Jiongyuan Li,Tianning Huang,Tian Huang,Nan Zhang,Yiran Li,Ziyu Xun,Zhe Zhu,Qiaorui Tan,Xuanyu Zhao,Liangwei Zou,Mingjian Piao,Chengjie Li,Boyu Sun,Jingwen Ma,Pengyao Chen,Jian Gu,Shipeng Dai,Hao Wang,Ming Ni,Haitao Zhao,Ling Lu
Glycolysis and protein lactylation both drive hepatocellular carcinoma (HCC) progression, yet their mechanistic interplay remains unclear. Through integrated single-cell and spatial transcriptomic analyses stratified by glycolytic activity, we identified alanyl-tRNA synthetase 1 (AARS1), a recently characterized protein lactyltransferase, as a key metabolic-immune regulator in HCC. Clinically, AARS1 is upregulated in tumors, correlates with elevated glycolytic flux measured by 18 F-fluorodeoxyglucose ( 18 F-FDG) positron emission tomography/computed tomography (PET/CT), poor prognosis, and immunotherapy resistance. In murine models, hepatocyte-specific knockout of AARS1 suppressed tumor growth and reduced the abundance of regulatory T cells (Tregs). Mechanistically, AARS1 catalyzes the lactylation of activating transcription factor 6 (ATF6) at lysine 424, preventing its degradation and leading to transcriptional activation of TDO2. This process promotes L-kynurenine production and supports Treg differentiation and function. Furthermore, L-kynurenine-AHR signaling drives eNAMPT secretion from Tregs, which augments tumor cell glycolysis and lactate production, thereby reinforcing a feedback loop that sustains AARS1-catalyzed ATF6 lactylation. Pharmacological inhibition of AARS1 with β-alanine sensitized tumors to PD-1/PD-L1 blockade.
✓ 已验证
DOI
PubMed
高影响因子
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