Transcription factor EB is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
that in humans is encoded by the ''TFEB''
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
.
Function
TFEB is a master gene for
lysosomal biogenesis
Spontaneous generation is a Superseded scientific theories, superseded scientific theory that held that living creatures could arise from abiotic component, non-living matter and that such processes were commonplace and regular. It was Hypoth ...
.
It encodes a
transcription factor
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription (genetics), transcription of genetics, genetic information from DNA to messenger RNA, by binding t ...
that coordinates expression of lysosomal hydrolases, membrane proteins and genes involved in
autophagy
Autophagy (or autophagocytosis; from the Greek language, Greek , , meaning "self-devouring" and , , meaning "hollow") is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-depe ...
.
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.
TFEB overexpression in cultured cells induces lysosomal biogenesis, exocytosis and autophagy.
In bacterial infection
nicotinic acid adenine dinucleotide phosphate (NAADP) induction of lysosomal Ca
2+ efflux and TFEB activation leads to enhanced expression of
inflammatory cytokine
Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling.
Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...
s.
Viral-mediated TFEB overexpression in cellular and mouse models of lysosomal storage disorders and in common neurodegenerative diseases such as
Huntington,
Parkinson and
Alzheimer
Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...
diseases, resulted in intracellular clearance of accumulating molecules and rescue of disease phenotypes.
TFEB is activated by
PGC1-alpha and promotes reduction of
htt aggregation and
neurotoxicity
Neurotoxicity is a form of toxicity in which a biological, chemical, or physical agent produces an adverse effect on the structure or function of the central and/or peripheral nervous system. It occurs when exposure to a substance – specifical ...
in a mouse model of
Huntington disease.
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.
TFEB constitutive activation, due to FLCN mutations, drives renal cystogenesis and tumorigenesis in
Birt–Hogg–Dubé syndrome.
Nuclear localization and activity of TFEB is inhibited by serine phosphorylation by
mTORC1
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.
mTOR Complex 1 (mTORC1) is comp ...
and extracellular signal–regulated kinase 2 (
ERK2).
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.
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.
Nutrient depletion induces TFEB dephosphorylation and subsequent nuclear translocation via the phosphatase calcineurin.
TFEB nuclear export is mediated by CRM1 and is dependent on phosphorylation.
TFEB is also a target of the protein kinase
AKT/PKB.
phosphorylates TFEB at serine 467 and inhibits TFEB nuclear translocation.
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.
TFEB is activated in
Trex1-deficient cells via inhibition of
mTORC1
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.
mTOR Complex 1 (mTORC1) is comp ...
activity, resulting in an expanded lysosomal compartment.
References
Further reading
*
*
*
*
*
*
*
*
*
{{refend