Macro (Autophagy) is a catabolic process that relies on the cooperative function of two organelles: the lysosome and the autophagosome. The recent discovery of a transcriptional gene network that co-regulates the biogenesis and function of these two organelles, and the identification of transcription factors, miRNAs and epigenetic regulators of autophagy, demonstrated that this catabolic process is controlled by both transcriptional and post-transcriptional mechanisms. In this review article, we discuss the nuclear events that control autophagy, focusing particularly on the role of the MiT/TFE transcription factor family. In addition, we will discuss evidence suggesting that the transcriptional regulation of autophagy could be targeted for the treatment of human genetic diseases, such as lysosomal storage disorders (LSDs) and neurodegeneration.

The mechanistic target of rapamycin complex 1 (mTORC1) is recruited to the lysosome by Rag guanosine triphosphatases (GTPases) and regulates anabolic pathways in response to nutrients. We found that MiT/TFE transcription factors—master regulators of lysosomal and melanosomal biogenesis and autophagy—control mTORC1 lysosomal recruitment and activity by directly regulating the expression of RagD. In mice, this mechanism mediated adaptation to food availability after starvation and physical exercise and played an important role in cancer growth. Up-regulation of MiT/TFE genes in cells and tissues from patients and murine models of renal cell carcinoma, pancreatic ductal adenocarcinoma, and melanoma triggered RagD-mediated mTORC1 induction, resulting in cell hyperproliferation and cancer growth. Thus, this transcriptional regulatory mechanism enables cellular adaptation to nutrient availability and supports the energy-demanding metabolism of cancer cells.

The mechanistic target of rapamycin complex 1 (mTORC1) signaling hub integrates multiple environmental cues to modulate cell growth and metabolism. Over the past decade considerable knowledge has been gained on the mechanisms modulating mTORC1 lysosomal recruitment and activation. However, whether and how mTORC1 is able to elicit selective responses to diverse signals has remained elusive until recently. We discuss emerging evidence for a 'non-canonical' mTORC1 signaling pathway that controls the function of microphthalmia/transcription factor E (MiT-TFE) transcription factors, key regulators of cell metabolism. This signaling pathway is mediated by a specific mechanism of substrate recruitment, and responds to stimuli that appear to converge on the lysosomal surface. We discuss the relevance of this pathway in physiological and disease conditions.

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis and insulin resistance and there are currently no approved drugs for its treatment. Hyperactivation of mTOR complex 1 (mTORC1) and subsequent impairment of the transcription factor EB (TFEB)-mediated autophagy–lysosomal pathway (ALP) are implicated in the development of NAFLD. Accordingly, agents that augment hepatic TFEB transcriptional activity may have therapeutic potential against NAFLD. The objective of this study was to investigate the effects of nuciferine, a major active component from lotus leaf, on NAFLD and its underlying mechanism of action. Here we show that nuciferine activated ALP and alleviated steatosis, insulin resistance in the livers of NAFLD mice and palmitic acid-challenged hepatocytes in a TFEB-dependent manner. Mechanistic investigation revealed that nuciferine interacts with the Ragulator subunit hepatitis B X-interacting protein and impairs the interaction of the Ragulator complex with Rag GTPases, thereby suppressing lysosomal localization and activity of mTORC1, which activates TFEB-mediated ALP and further ameliorates hepatic steatosis and insulin resistance. Our present results indicate that nuciferine may be a potential agent for treating NAFLD and that regulation of the mTORC1–TFEB–ALP axis could represent a novel pharmacological strategy to combat NAFLD.

Birt‐Hogg‐Dubé (BHD) syndrome is an inherited familial cancer syndrome characterized by the development of cutaneous lesions, pulmonary cysts, renal tumors and cysts and caused by loss‐of‐function pathogenic variants in the gene encoding the tumor‐suppressor protein folliculin (FLCN). FLCN acts as a negative regulator of TFEB and TFE3 transcription factors, master controllers of lysosomal biogenesis and autophagy, by enabling their phosphorylation by the mechanistic Target Of Rapamycin Complex 1 (mTORC1). We have previously shown that deletion of Tfeb rescued the renal cystic phenotype of kidney‐specific Flcn KO mice. Using Flcn/Tfeb/Tfe3 double and triple KO mice, we now show that both Tfeb and Tfe3 contribute, in a differential and cooperative manner, to kidney cystogenesis. Remarkably, the analysis of BHD patient‐derived tumor samples revealed increased activation of TFEB/TFE3‐mediated transcriptional program and silencing either of the two genes rescued tumorigenesis in human BHD renal tumor cell line‐derived xenografts (CDXs). Our findings demonstrate in disease‐relevant models that both TFEB and TFE3 are key drivers of renal tumorigenesis and suggest novel therapeutic strategies based on the inhibition of these transcription factors.

Neurodegeneration is a prominent feature of lysosomal storage disorders (LSDs). Emerging data identify autophagy dysfunction in neurons as a major component of the phenotype. However, the autophagy pathway in the CNS has been studied predominantly in neurons, whereas in other cell types it has been largely unexplored. We studied the lysosome-autophagic pathway in astrocytes from a murine model of multiple sulfatase deficiency (MSD), a severe form of LSD. Similar to what was observed in neurons, we found that lysosomal storage in astrocytes impairs autophagosome maturation and this, in turn, has an impact upon the survival of cortical neurons and accounts for some of the neurological features found in MSD. Thus, our data indicate that lysosomal/autophagic dysfunction in astrocytes is an important component of neurodegeneration in LSDs.