Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, Jiangsu, China.
Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu, China.
Autophagy. 2021 Sep;17(9):2475-2493. doi: 10.1080/15548627.2020.1831815. Epub 2020 Oct 21.
TFE3 (transcription factor binding to IGHM enhancer 3) nuclear translocation and transcriptional activity has been implicated in PINK1-PRKN/parkin-dependent mitophagy. However, the transcriptional control governing the mitophagy in TFE3/Xp11.2 translocation renal cell carcinoma ( tRCC) is largely unknown. Here, we investigated the role and mechanisms of PRCC-TFE3 fusion protein, one of TFE3 fusion types in TFE3 tRCC, in governing mitophagy to promote development of tRCC. We observed and analyzed mitophagy, transcriptional control of PRCC-TFE3 on PINK1-PRKN-dependent mitophagy, PRCC-TFE3 fusions nuclear translocation, cancer cell survival and proliferation under mitochondrial oxidative damage in tRCC cell line. We found that nuclear-aggregated PRCC-TFE3 fusions constitutively activated expression of the target gene E3 ubiquitin ligase , leading to rapid PINK1-PRKN-dependent mitophagy that promoted cell survival under mitochondrial oxidative damage as well as cell proliferation through decreasing mitochondrial ROS formation. However, nuclear translocation of TFE3 fusions escaped from PINK1-PRKN-dependent mitophagy. Furthermore, we confirmed that PRCC-TFE3 fusion accelerated mitochondrial turnover by activating PPARGC1A/PGC1α-NRF1. In conclusion, our findings indicated a major role of PRCC-TFE3 fusion-mediated mitophagy and mitochondrial biogenesis in promoting proliferation of tRCC.
TFE3（转录因子结合 IGHM 增强子 3）核易位及其转录活性与 PINK1-PRKN/parkin 依赖性线粒体自噬有关。然而，TFE3/Xp11.2 易位肾细胞癌（tRCC）中调节线粒体自噬的转录控制在很大程度上尚不清楚。在这里，我们研究了 PRCC-TFE3 融合蛋白（TFE3 融合类型之一）在调节线粒体自噬以促进 tRCC 发展中的作用和机制。我们观察和分析了线粒体自噬、PRCC-TFE3 对 PINK1-PRKN 依赖性线粒体自噬的转录控制、PRCC-TFE3 融合核易位、线粒体氧化损伤下 tRCC 细胞系中的癌细胞存活和增殖。我们发现核聚集的 PRCC-TFE3 融合蛋白持续激活靶基因 E3 泛素连接酶的表达，导致快速的 PINK1-PRKN 依赖性线粒体自噬，从而促进线粒体氧化损伤下的细胞存活以及通过减少线粒体 ROS 形成来促进细胞增殖。然而，TFE3 融合核易位逃避了 PINK1-PRKN 依赖性线粒体自噬。此外，我们证实 PRCC-TFE3 融合通过激活 PPARGC1A/PGC1α-NRF1 加速线粒体周转。总之，我们的研究结果表明 PRCC-TFE3 融合介导的线粒体自噬和线粒体生物发生在促进 tRCC 增殖中起主要作用。
