The Oncogene Transcription Factor EB Regulates Vascular Functions

Abstract

Transcription factor EB (TFEB) represents an emerging player in vascular biology. It belongs to the bHLH-leucine zipper transcription factor microphthalmia family, which includes microphthalmia-associated transcription factor, transcription factor E3 and transcription factor EC, and is known to be deregulated in cancer. The canonical transcriptional pathway orchestrated by TFEB adapts cells to stress in all kinds of tissues by supporting lysosomal and autophagosome biogenesis. However, emerging findings highlight that TFEB activates other genetic programs involved in cell proliferation, metabolism, inflammation and immunity. Here, we first summarize the general principles and mechanisms by which TFEB activates its transcriptional program. Then, we analyze the current knowledge of TFEB in the vascular system, placing particular emphasis on its regulatory role in angiogenesis and on the involvement of the vascular unit in inflammation and atherosclerosis.

TFEB Signalling-Related MicroRNAs and Autophagy

“…ChIP-seq analysis of TFEB protein interactors profiling TFEB-mediated transcriptional regulation and genome-wide mapping of TFEB target sites and co-expression analyses [11,12] revealed that TFEB interactors can be associated in different gene categories involved in autophagy and lysosomal activities and biogenesis, as detailed above [11][12][13][14][15][16]. TFEB coordinates the expression of approximately 60 lysosomal hydrolases, as well as lysosomal and autophagosome membrane and accessory proteins [11][12][13][14][15][16], but also regulates vesicles formation, localisation, and flux [11][12][13][14][15][16]. Interestingly, numerous genes have related TFEB to the modulation of endoplasmic reticulum (ER) stress, as well as cellular metabolism [17,18], cellular proliferation, DNA replication, and cytoskeletal regulation [12].…”

“…In vitro and vivo studies have suggested TFEB as an important regulator of various cellular physiological and pathological processes in addiction to autophagy. TFEB supports metabolism, immunity, angiogenesis, inflammation, and cancer development [15][16][17][18][19][20][21].…”

“…In vitro and vivo studies have suggested TFEB as an important regulator of various cellular physiological and pathological processes in addiction to autophagy. TFEB supports metabolism, immunity, angiogenesis, inflammation, and cancer development [15][16][17][18][19][20][21]. TFEB activation occurs in response to multiple stress factors such as nutrient and growth factors alterations, hypoxia, and mitochondrial stress.…”

“…The transcription factor action results from its cytosol-nuclear translocation mediated by a post-translational regulation by protein modifications and protein-protein interactions. Moreover, the cellular and nuclear amount of TFEB is also important: a transcriptional and post-transcriptional TFEB modulation is increasingly evident [11][12][13][14][15][16]. Multiple pathways intertwine, resulting in TFEB phosphorylation at residues S122, S142, and S211, which address its sub-cellular localisation (Figure 2) [11][12][13][14][15][16].…”

“…Moreover, the cellular and nuclear amount of TFEB is also important: a transcriptional and post-transcriptional TFEB modulation is increasingly evident [11][12][13][14][15][16]. Multiple pathways intertwine, resulting in TFEB phosphorylation at residues S122, S142, and S211, which address its sub-cellular localisation (Figure 2) [11][12][13][14][15][16]. (STAT1), and by Krüppel-like factor 2 (KLF2) [11][12][13][14][15][16].…”