Identification of Transcription Factor E3 (TFE3) as a Receptor-independent Activator of Gα16: GENE REGULATION BY NUCLEAR Gα SUBUNIT AND ITS ACTIVATOR*

摘要

Receptor-independent G-protein regulators provide diverse mechanisms for signal input to G-protein-based signaling systems, revealing unexpected functional roles for G-proteins. As part of a broader effort to identify disease-specific regulators for heterotrimeric G-proteins, we screened for such proteins in cardiac hypertrophy using a yeast-based functional screen of mammalian cDNAs as a discovery platform. We report the identification of three transcription factors belonging to the same family, transcription factor E3 (TFE3), microphthalmia-associated transcription factor, and transcription factor EB, as novel receptor-independent activators of G-protein signaling selective for Gα16. TFE3 and Gα16 were both up-regulated in cardiac hypertrophy initiated by transverse aortic constriction. In protein interaction studies in vitro, TFE3 formed a complex with Gα16 but not with Gαi3 or Gαs. Although increased expression of TFE3 in heterologous systems had no influence on receptor-mediated Gα16 signaling at the plasma membrane, TFE3 actually translocated Gα16 to the nucleus, leading to the induction of claudin 14 expression, a key component of membrane structure in cardiomyocytes. The induction of claudin 14 was dependent on both the accumulation and activation of Gα16 by TFE3 in the nucleus. These findings indicate that TFE3 and Gα16 are up-regulated under pathologic conditions and are involved in a novel mechanism of transcriptional regulation via the relocalization and activation of Gα16.