Identification of Transcription Factor E3 (TFE3) as a Receptor-independent Activator of Gα16

Abstract

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 G␣ 16 . TFE3 and G␣ 16 were both up-regulated in cardiac hypertrophy initiated by transverse aortic constriction. In protein interaction studies in vitro, TFE3 formed a complex with G␣ 16 but not with G␣ i3 or G␣ s . Although increased expression of TFE3 in heterologous systems had no influence on receptormediated G␣ 16 signaling at the plasma membrane, TFE3 actually translocated G␣ 16 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 G␣ 16 by TFE3 in the nucleus. These findings indicate that TFE3 and G␣ 16 are up-regulated under pathologic conditions and are involved in a novel mechanism of transcriptional regulation via the relocalization and activation of G␣ 16 .

Activator of G-protein signaling 8 is involved in VEGF-mediated signal processing during angiogenesis

“…Transcription factor E3 (TFE3, also known as AGS11), which was isolated from murine hypertrophied heart, selectively forms a complex with the Gα 16 subunit (Sato et al, 2011). TFE3-Gα 16 is associated with the induction of claudin-14 through an new type of transcriptional regulation (Sato et al, 2011).…”

“…Transcription factor E3 (TFE3, also known as AGS11), which was isolated from murine hypertrophied heart, selectively forms a complex with the Gα 16 subunit (Sato et al, 2011). TFE3-Gα 16 is associated with the induction of claudin-14 through an new type of transcriptional regulation (Sato et al, 2011). Regulators of G-protein signaling (RGSs), a family of proteins that accelerate the GTPase activity of the Gα subunit leading to inhibition of G-protein signaling, are involved in hypertension, cardiac hypertrophy and/or hypoxiamediated injury (Wieland and Mittmann, 2003;Gu et al, 2009;Zhang and Mende, 2011).…”

Roles of Accessory Proteins for Heterotrimeric G-Protein in the Development of Cardiovascular Diseases

“…Gα16 is enriched in hematopoietic tissue; however, it is also expressed in the heart 68, 69 and induced in response to pressure overload. 24 Interestingly, TFE3 translocates Gα16 to the nucleus in association with increased expression of claudin-14, a key component of membrane structure in cardiomyocytes. Upon pressure overload stress, claudin-14 increases with accompanying upregulation of TFE3 and Gα16 in the heart.…”

“…22 We subsequently focused on identifying accessory proteins for G-proteins that are induced in the myocardium exposed to repetitive transient ischemia 23 as well as pressure overload. 24 These accessory proteins influence the activation or deactivation of the Gα subunit or form complexes with Gα or Gβ γ distinct from the typical Gαβ γ heterotrimer. Accumulating data suggest that accessory proteins for G-proteins provide additional signal input to the G-protein signaling system in the absence of GPCRs or act as alternative binding partners of G-protein subunits serving roles yet to be determined.…”

“…67 TFE3 (AGS11) TFE3 (AGS11) was identified as a novel activator of G-protein signaling (AGS) in the hypertrophied mouse heart induced by transverse aortic constriction. 24 Although TFE3 is a well-known nuclear transcription factor, it selectively forms a complex with Gα16 but not Gαi3, Gαs, or Gαq. Gα16 is enriched in hematopoietic tissue; however, it is also expressed in the heart 68, 69 and induced in response to pressure overload.…”