The positive regulation loop between NRF1 and NONO-TFE3 fusion promotes phase separation and aggregation of NONO-TFE3 in NONO-TFE3 tRCC.

TFE3 gene fusions often place TFE3 under the control of a more active promoter and cause overexpression of the TFE3 proteins in renal cell carcinoma associated with Xp11.2 translocations (Xp11.2 tRCC). The purpose of this study was to investigate the transcriptional regulation and aggregation mechanism of NONO-TFE3 in NONO-TFE3 tRCC. In this study, we found that the nuclear aggregation of NONO-TFE3 fusion was significantly more than that of intact TFE3 or PRCC-TFE3 fusion. We observed that NONO fragment mediated-phase separation promoted stabilization and aggregation of NONO-TFE3 fusion. Meantime, we revealed that the positive regulation loop between NONO-TFE3 and NRF1 increased mitochondrial biosynthesis and metabolism in NONO-TFE3 tRCC. Therefore, the present study raises the possibility that mitochondrial metabolism is potentially a fruitful arena for NONO-TFE3 tRCC therapy.