TFEB Links Autophagy to Lysosomal Biogenesis

Abstract

Autophagy is a cellular catabolic process that relies on the cooperation of autophagosomes and lysosomes. During starvation, the cell expands both compartments to enhance degradation processes. We found that starvation activates a transcriptional program that controls major steps of the autophagic pathway, including autophagosome formation, autophagosome-lysosome fusion and substrate degradation. The transcription factor EB (TFEB), a master gene for lysosomal biogenesis, coordinated this program by driving expression of autophagy and lysosomal genes. Nuclear localization and activity of TFEB were regulated by serine phosphorylation mediated by the extracellular signal-regulated kinase 2, whose activity was tuned by the levels of extracellular nutrients. Thus, a mitogen-activated protein kinase-dependent mechanism regulates autophagy by controlling the biogenesis and partnership of two distinct cellular organelles.

Advanced glycation end‐products suppress autophagic flux in podocytes by activating mammalian target of rapamycin and inhibiting nuclear translocation of transcription factor EB

“…Because TFEB, the ‘master regulator’ of autophagy, controls multiple steps of the autophagic pathway 10, we speculated that it might participate in AGE‐regulated autophagy.…”

AMPK activation protects cells from oxidative stress‐induced senescence via autophagic flux restoration and intracellular NAD + elevation

“…Recently, transcription factor EB (TFEB) was discovered as a master regulator of lysosomal and autophagic function (Settembre et al ., 2011), and its nuclear distribution following mTOR inactivation is an accepted mechanistic explanation for the activation of autophagy (Roczniak‐Ferguson et al ., 2012; Medina et al ., 2015). According to this mTOR‐TFEB axis theory, mTOR inactivation‐induced TFEB dephosphorylation leads to TFEB translocation to the nucleus, which activates the transcription of specific lysosomal genes (Settembre et al ., 2011). Unexpectedly, the relationship between mTOR and TFEB in our system does not appear to fit this paradigm.…”

Trehalose reduces retinal degeneration, neuroinflammation and storage burden caused by a lysosomal hydrolase deficiency

“…TFEB (transcription factor EB) is a master regulator of lysosomal pathways, governing lysosomal biogenesis and metabolism [17], autophagy [18], and lysosomal exocytosis [19] and proteostasis [20]. TFEB overexpression promotes lysosomal proliferation and enhances degradative capabilities against lysosomal or autophagic substrates (such as glycosaminoglycans, polyQ-expanded HTT (huntingtin), and ceroid lipopigments), and rescues affected neurons in animal models of proteinopathies [17,21–27].…”