Upregulation of the TFEB-mediated lysosome function relieves 4-Hydroxynonenal-Induced apoptosis.

4-Hydroxynonenal (4-HNE), the most toxic end-product of lipid peroxidation formed during oxidative stress, has been implicated in many diseases including neurodegenerative diseases, metabolic diseases, myocardial diseases, cancer and age-related diseases. 4-HNE can actively react with DNA, proteins and lipids, causing rapid cell death. The accumulation of 4-HNE leads to induction of autophagy, which clears damaged proteins and organelles. However, the underlying mechanism of 4-HNE-regulated autophagy is still not known. Transcriptional factor EB (TFEB) is a master regulator of lysosomal and autophagic functions, which we show here that TFEB is activated by 4-HNE. 4-HNE induces TFEB nuclear translocation and activated TFEB then upregulates the expression of genes required for autophagic and lysosomal biogenesis and function. Reactive oxygen species and Ca2+ are required in this process and TFEB activity is required for 4-HNE-mediated lysosomal function. Most importantly, genetic inhibition of TFEB (TFEB-KO) exacerbates 4-HNE-induced cell death, suggesting that TFEB is essential for cellular adaptive response to 4-HNE-induced cell damage. Hence, targeting TFEB to promote autophagic and lysosomal function may represent a promising approach to treat neurodegenerative and metabolic diseases in which 4-HNE accumulation has been implicated.

Reactive Oxygen Species as a Link between Antioxidant Pathways and Autophagy.

Reactive oxygen species (ROS) are highly reactive molecules that can oxidize proteins, lipids, and DNA. Under physiological conditions, ROS are mainly generated in the mitochondria during aerobic metabolism. Under pathological conditions, excessive ROS disrupt cellular homeostasis. High levels of ROS result in severe oxidative damage to the cellular machinery. However, a low/mild level of ROS could serve as a signal to trigger cell survival mechanisms. To prevent and cope with oxidative damage to biomolecules, cells have developed various antioxidant and detoxifying mechanisms. Meanwhile, ROS can initiate autophagy, a process of self-clearance, which helps to reduce oxidative damage by engulfing and degrading oxidized substance. This review summarizes the interactions among ROS, autophagy, and antioxidant pathways. The effects of natural phytochemicals on autophagy induction, antioxidation, and dual-function are also discussed.

Resveratrol promotes lysosomal function via ER calcium-dependent TFEB activation to ameliorate lipid accumulation.

Abnormal lipid accumulation is associated to the development of metabolic diseases such as hepatic steatosis and lipid storage diseases. Pharmacological agents that can attenuate lipid accumulation therefore have therapeutic potentials for these diseases. Resveratrol (RSV), a natural active substance found in fruits and nuts, has been reported to effectively reduce the intracellular lipid accumulation, but the underlying mechanisms of RSV remain elusive. Here, we show that RSV triggers an endoplasmic reticulum (ER)- Ca2+ signaling that activates transcriptional factor EB (TFEB), a master transcriptional regulator of autophagic and lysosomal biogenesis. Moreover, RSV activates protein phosphatase 2A (PP2A), which binds and dephosphorylates TFEB, promoting its nuclear translocation and the expression of TFEB target genes required for autophagosome and lysosomal biogenesis. Notably, genetic inhibition of TFEB significantly ameliorates RSV-mediated lipid clearance. Taken together, these data link RSV-induced ER calcium signaling, PP2A and TFEB activation to promote autophagy and lysosomal function, by which RSV may trigger a cellular self-defense mechanism that effectively mitigate lipid accumulation commonly associated with many metabolic diseases.

TFEB Biology and Agonists at a Glance.

Autophagy is a critical regulator of cellular survival, differentiation, development, and homeostasis, dysregulation of which is associated with diverse diseases including cancer and neurodegenerative diseases. Transcription factor EB (TFEB), a master transcriptional regulator of autophagy and lysosome, can enhance autophagic and lysosomal biogenesis and function. TFEB has attracted a lot of attention owing to its ability to induce the intracellular clearance of pathogenic factors in a variety of disease models, suggesting that novel therapeutic strategies could be based on the modulation of TFEB activity. Therefore, TFEB agonists are a promising strategy to ameliorate diseases implicated with autophagy dysfunction. Recently, several TFEB agonists have been identified and preclinical or clinical trials are applied. In this review, we present an overview of the latest research on TFEB biology and TFEB agonists.