Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Department of Biology and Academy for Advanced Interdisciplinary Studies, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China.
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, 15261, USA.
Nat Commun. 2019 Feb 19;10(1):845. doi: 10.1038/s41467-019-08772-3.
Cell metabolism is strongly influenced by mechano-environment. We show here that a fraction of kindlin-2 localizes to mitochondria and interacts with pyrroline-5-carboxylate reductase 1 (PYCR1), a key enzyme for proline synthesis. Extracellular matrix (ECM) stiffening promotes kindlin-2 translocation into mitochondria and its interaction with PYCR1, resulting in elevation of PYCR1 level and consequent increase of proline synthesis and cell proliferation. Depletion of kindlin-2 reduces PYCR1 level, increases reactive oxygen species (ROS) production and apoptosis, and abolishes ECM stiffening-induced increase of proline synthesis and cell proliferation. In vivo, both kindlin-2 and PYCR1 levels are markedly increased in lung adenocarcinoma. Ablation of kindlin-2 in lung adenocarcinoma substantially reduces PYCR1 and proline levels, and diminishes fibrosis in vivo, resulting in marked inhibition of tumor growth and reduction of mortality rate. Our findings reveal a mechanoresponsive kindlin-2-PYCR1 complex that links mechano-environment to proline metabolism and signaling, and suggest a strategy to inhibit tumor growth.
细胞代谢受机械环境的强烈影响。我们在这里表明，黏着斑蛋白-2 的一部分定位于线粒体，并与吡咯啉-5-羧酸还原酶 1（PYCR1）相互作用，PYCR1 是脯氨酸合成的关键酶。细胞外基质（ECM）变硬促进黏着斑蛋白-2 向线粒体的易位及其与 PYCR1 的相互作用，导致 PYCR1 水平升高，继而脯氨酸合成和细胞增殖增加。黏着斑蛋白-2 的耗竭会降低 PYCR1 水平，增加活性氧（ROS）的产生和细胞凋亡，并消除 ECM 变硬诱导的脯氨酸合成和细胞增殖增加。在体内，肺腺癌中黏着斑蛋白-2 和 PYCR1 的水平明显升高。肺腺癌中黏着斑蛋白-2 的缺失会显著降低 PYCR1 和脯氨酸的水平，并减少体内纤维化，从而显著抑制肿瘤生长和降低死亡率。我们的发现揭示了一个机械响应性黏着斑蛋白-2-PYCR1 复合物，它将机械环境与脯氨酸代谢和信号联系起来，并为抑制肿瘤生长提供了一种策略。
