Transcription factor EB is a protein that in humans is encoded by the TFEB gene. [5] [6]
Transcription factor EB is a protein that in humans is encoded by the TFEB gene. [5] [6]
TFEB is a master gene for lysosomal biogenesis. [7] It encodes a transcription factor that coordinates expression of lysosomal hydrolases, membrane proteins and genes involved in autophagy. [7] [8] Upon nutrient depletion and under aberrant lysosomal storage conditions such as in lysosomal storage diseases, TFEB translocates from the cytoplasm to the nucleus, resulting in the activation of its target genes. [7] [8] TFEB overexpression in cultured cells induces lysosomal biogenesis, exocytosis and autophagy. [7] [8] [9]
In bacterial infection nicotinic acid adenine dinucleotide phosphate (NAADP) induction of lysosomal Ca2+ efflux and TFEB activation leads to enhanced expression of inflammatory cytokines. [10] Viral-mediated TFEB overexpression in cellular and mouse models of lysosomal storage disorders and in common neurodegenerative diseases such as Huntington, Parkinson and Alzheimer diseases, resulted in intracellular clearance of accumulating molecules and rescue of disease phenotypes. [7] [9] [11] [12] [13] TFEB is activated by PGC1-alpha and promotes reduction of htt aggregation and neurotoxicity in a mouse model of Huntington disease. [14] TFEB overexpression has been found in patients with renal cell carcinoma and pancreatic cancer and was shown to promote tumorogenesis via induction of various oncogenic signals. [15] [16] [17]
TFEB constitutive activation, due to FLCN mutations, drives renal cystogenesis and tumorigenesis in Birt–Hogg–Dubé syndrome. [18]
Nuclear localization and activity of TFEB is inhibited by serine phosphorylation by mTORC1 and extracellular signal–regulated kinase 2 (ERK2). [8] [19] [20] [21] mTORC1 phosphorylation of TFEB occurs at the lysosomal surface, both of which are localized there by interaction with the Rag GTPases. Phosphorylated TFEB is then retained in the cytosol by interaction with 14-3-3 proteins. [20] [22] [21] These kinases are tuned to the levels of extracellular nutrients suggesting a coordination in regulation of autophagy and lysosomal biogenesis and partnership of two distinct cellular organelles. [8] Nutrient depletion induces TFEB dephosphorylation and subsequent nuclear translocation via the phosphatase calcineurin. [23] TFEB nuclear export is mediated by CRM1 and is dependent on phosphorylation. [24] [25] TFEB is also a target of the protein kinase AKT/PKB. [26] AKT/PKB phosphorylates TFEB at serine 467 and inhibits TFEB nuclear translocation. [26] Pharmacological inhibition of AKT/PKB activates TFEB, promotes lysosome biogenesis and autophagy, and ameliorates neuropathology in mouse models of Juvenile Batten disease and Sanfilippo syndrome type B. [26] [27] TFEB is activated in Trex1-deficient cells via inhibition of mTORC1 activity, resulting in an expanded lysosomal compartment. [28]
A lysosome is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that digest many kinds of biomolecules. A lysosome has a specific composition, of both its membrane proteins and its lumenal proteins. The lumen's pH (~4.5–5.0) is optimal for the enzymes involved in hydrolysis, analogous to the activity of the stomach. Besides degradation of polymers, the lysosome is involved in cell processes of secretion, plasma membrane repair, apoptosis, cell signaling, and energy metabolism.
Autophagy is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-dependent regulated mechanism. It allows the orderly degradation and recycling of cellular components. Although initially characterized as a primordial degradation pathway induced to protect against starvation, it has become increasingly clear that autophagy also plays a major role in the homeostasis of non-starved cells. Defects in autophagy have been linked to various human diseases, including neurodegeneration and cancer, and interest in modulating autophagy as a potential treatment for these diseases has grown rapidly.
Protein kinase B (PKB), also known as Akt, is the collective name of a set of three serine/threonine-specific protein kinases that play key roles in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, transcription, and cell migration.
The mammalian target of rapamycin (mTOR), also referred to as the mechanistic target of rapamycin, and sometimes called FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1), is a kinase that in humans is encoded by the MTOR gene. mTOR is a member of the phosphatidylinositol 3-kinase-related kinase family of protein kinases.
Microphthalmia-associated transcription factor also known as class E basic helix-loop-helix protein 32 or bHLHe32 is a protein that in humans is encoded by the MITF gene.
The tumor suppressor gene FLCN encodes the protein folliculin, also known as Birt–Hogg–Dubé syndrome protein, which functions as an inhibitor of Lactate Dehydrogenase-A and a regulator of the Warburg effect. Folliculin (FLCN) is also associated with Birt–Hogg–Dubé syndrome, which is an autosomal dominant inherited cancer syndrome in which affected individuals are at risk for the development of benign cutaneous tumors (folliculomas), pulmonary cysts, and kidney tumors.
Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is a protein that in humans is encoded by the PPARGC1A gene. PPARGC1A is also known as human accelerated region 20 (HAR20). It may, therefore, have played a key role in differentiating humans from apes.
Tuberous Sclerosis Complex 2 (TSC2), also known as Tuberin, is a protein that in humans is encoded by the TSC2 gene.
Transcription factor E3 is a protein that in humans is encoded by the TFE3 gene.
Regulatory-associated protein of mTOR also known as raptor or KIAA1303 is an adapter protein that is encoded in humans by the RPTOR gene. Two mRNAs from the gene have been identified that encode proteins of 1335 and 1177 amino acids long.
Protein CLN8 is a protein that in humans is encoded by the CLN8 gene.
ULK1 is an enzyme that in humans is encoded by the ULK1 gene.
The Akt signaling pathway or PI3K-Akt signaling pathway is a signal transduction pathway that promotes survival and growth in response to extracellular signals. Key proteins involved are PI3K and Akt.
Chaperone-mediated autophagy (CMA) refers to the chaperone-dependent selection of soluble cytosolic proteins that are then targeted to lysosomes and directly translocated across the lysosome membrane for degradation. The unique features of this type of autophagy are the selectivity on the proteins that are degraded by this pathway and the direct shuttling of these proteins across the lysosomal membrane without the requirement for the formation of additional vesicles.
mTORC1, also known as mammalian target of rapamycin complex 1 or mechanistic target of rapamycin complex 1, is a protein complex that functions as a nutrient/energy/redox sensor and controls protein synthesis.
Andrea Ballabio is an Italian scientist and academic professor. He is director of the Telethon Institute of Genetics and Medicine (TIGEM) of Pozzuoli; professor of medical genetics at the Federico II University of Naples and visiting professor of genetics at Baylor College of Medicine in Houston, Texas, US and at the University of Oxford-UK.
Late endosomal/lysosomal adaptor, MAPK and MTOR activator 1 is a protein that in humans is encoded by the LAMTOR1 gene.
ML-SI3 is a chemical compound which acts as an "antagonist" of the TRPML family of calcium channels, with greatest activity at the TRPML1 channel, although it also blocks the related TRPML2 and TRPML3 channels with lower affinity. It is used for research into the role of TRPML1 and its various functions in lysosomes and elsewhere in the body.
Phosphatidylinositol 3-phosphate-binding protein 2 (Pib2) is a yeast protein involved in the regulation of TORC1 signaling and lysosomal membrane permeabilization. It is essential for the reactivation of TORC1 following exposure to rapamycin or nutrient starvation.
AMBRA1 is a protein that is able to regulate cancer cells through autophagy. AMBRA1 is described as a mechanism cells use to divide and there is new evidence demonstrating the role and impact of AMBRA1 as a candidate for the treatment of several disorders and diseases, including anticancer therapy. It is known to suppress tumors and plays a role in mitophagy and apoptosis. AMBRA1 can be found in the cytoskeleton and mitochondria and during the process of autophagy, it is localized at the endoplasmic reticulum. In normal conditions, AMBRA1 is dormant and will bind to BCL2 in the outer membrane. This relocation enables autophagosome nucleation. AMBRA1 protein is involved in several cellular processes and is involved in the regulation of the immune system and nervous system.
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