Interaction between poly(A)-binding protein PABPC4 and nuclear receptor corepressor NCoR1 modulates a metabolic stress response.
Interaction between poly(A)-binding protein PABPC4 and nuclear receptor corepressor NCoR1 modulates a metabolic stress response.
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DOI：
10.1016/j.jbc.2023.104702
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发表时间：
2023-06
影响因子：
4.8
通讯作者：
Silveira, L R
中科院分区：
文献类型：
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作者：
Oliveira, A G;Oliveira, L D;Cruz, M V;Guimaraes, D S P S F;Lima, T I;Santos-Favero, B C;Luchessi, A D;Pauletti, B A;Leme, A P;Bajgelman, M C;Afonso, J;Regitano, L C A;Carvalho, H F;Carneiro, E M;Kobarg, J;Perissi, V;Auwerx, J;Silveira, L R
线粒体是已知的细胞器，主要通过氧化磷酸化过程产生ATP。环境信号被整个生物体或细胞感知，并显著影响这一过程，导致基因转录的变化，从而改变线粒体的功能和生物发生。线粒体基因的表达受核转录因子的精细调控，包括核受体及其辅助调节因子。其中最著名的协调制子是核受体辅阻遏子1(NCoR1)。在小鼠中，肌肉特异性的NCoR1基因敲除可以诱导氧化表型，改善葡萄糖和脂肪酸代谢。然而，NCoR1的调控机制仍然不清楚。在这项工作中，我们鉴定了聚(A)结合蛋白4(PABPC4)是一种新的NCoR1相互作用元件。出乎意料的是，我们发现PABPC4的沉默诱导了C2C12和MEF细胞的氧化表型，表现为氧耗增加，线粒体含量增加，乳酸产生减少。从机制上讲，我们证明了PABPC4的沉默增加了NCoR1的泛素化和随之而来的降解，导致了PPAR调节基因的去抑制。结果，PABPC4沉默的细胞有更大的代谢脂类的能力，减少了细胞内的脂滴，并减少了细胞死亡。有趣的是，在已知的诱导线粒体功能和生物发生的条件下，mRNA表达和PABPC4蛋白含量都显著降低。因此，我们的研究表明，PABPC4表达的降低可能是一种适应性事件，需要诱导线粒体活动来响应骨骼肌细胞的代谢应激。因此，NCoR1-PABPC4界面可能是治疗代谢性疾病的一条新途径。
Mitochondria are organelles known primarily for generating ATP via the oxidative phosphorylation process. Environmental signals are sensed by whole organisms or cells and markedly affect this process, leading to alterations in gene transcription and, consequently, changes in mitochondrial function and biogenesis. The expression of mitochondrial genes is finely regulated by nuclear transcription factors, including nuclear receptors and their coregulators. Among the best-known coregulators is the nuclear receptor corepressor 1 (NCoR1). Muscle-specific knockout of NCoR1 in mice induces an oxidative phenotype, improving glucose and fatty acid metabolism. However, the mechanism by which NCoR1 is regulated remains elusive. In this work, we identified the poly(A)–binding protein 4 (PABPC4) as a new NCoR1 interactor. Unexpectedly, we found that silencing of PABPC4 induced an oxidative phenotype in both C2C12 and MEF cells, as indicated by increased oxygen consumption, mitochondria content, and reduced lactate production. Mechanistically, we demonstrated that PABPC4 silencing increased the ubiquitination and consequent degradation of NCoR1, leading to the derepression of PPAR-regulated genes. As a consequence, cells with PABPC4 silencing had a greater capacity to metabolize lipids, reduced intracellular lipid droplets, and reduced cell death. Interestingly, in conditions known to induce mitochondrial function and biogenesis, both mRNA expression and PABPC4 protein content were markedly reduced. Our study, therefore, suggests that the lowering of PABPC4 expression may represent an adaptive event required to induce mitochondrial activity in response to metabolic stress in skeletal muscle cells. As such, the NCoR1–PABPC4 interface might be a new road to the treatment of metabolic diseases.