ABSTRACT

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 (TFE3 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 PRCC-TFE3 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 PRCC-TFE3 tRCC cell line. We found that nuclear-aggregated PRCC-TFE3 fusions constitutively activated expression of the target gene E3 ubiquitin ligase PRKN, 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 PRCC-TFE3 tRCC.

摘要

TFE3（与 IGHM 增强子 3 结合的转录因子）核转位和转录活性与 PINK1-PRKN/parkin 依赖性线粒体自噬有关。然而，控制 TFE3/Xp11.2 易位肾细胞癌 ( TFE3 tRCC) 中线粒体自噬的转录控制在很大程度上是未知的。在这里，我们研究了 PRCC-TFE3 融合蛋白（TFE3 tRCC 中的 TFE3 融合类型之一）在调控线粒体自噬以促进PRCC-TFE3 tRCC 发育中的作用和机制。我们观察并分析了线粒体自噬、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、PRCC- TFE3线粒体氧化损伤下癌细胞的存活和增殖tRCC 细胞系。我们发现核聚集的PRCC-TFE3融合组成性地激活了靶基因E3泛素连接酶PRKN的表达，导致快速依赖PINK1-PRKN的线粒体自噬，从而促进细胞在线粒体氧化损伤下的存活以及通过减少线粒体ROS形成来促进细胞增殖。然而，TFE3 融合的核转位从 PINK1-PRKN 依赖性线粒体自噬中逃脱。此外，我们证实PRCC-TFE3融合通过激活PPARGC1A/PGC1α-NRF1加速线粒体更新。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PRCC-TFE3 tRCC增殖中的主要作用。