RNA-binding protein FUS/TLS (FUused in Sarcoma/Translocated in LipoSarcoma), also known as heterogeneous nuclear ribonucleoprotein P2 is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, res ...
that in humans is encoded by the ''FUS''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
.
Discovery
FUS/TLS was initially identified as a
fusion protein
Fusion proteins or chimeric (kī-ˈmir-ik) proteins (literally, made of parts from different sources) are proteins created through the joining of two or more genes that originally coded for separate proteins. Translation of this '' fusion gene'' ...
(FUS-CHOP) produced as a result of chromosomal translocations in human cancers, especially
liposarcoma
Liposarcomas are the most common subtype of soft tissue sarcomas, accounting for at least 20% of all sarcomas in adults. Soft tissue sarcomas are rare neoplasms with over 150 different histological subtypes or forms. Liposarcomas arise from the pr ...
s.
In these instances, the promoter and N-terminal part of FUS/TLS is translocated to the C-terminal domain of various DNA-binding transcription factors (e.g.
CHOP) conferring a strong transcriptional activation domain onto the fusion proteins.
FUS/TLS was independently identified as the hnRNP P2 protein, a subunit of a complex involved in the maturation of
pre-mRNA
A primary transcript is the single-stranded ribonucleic acid ( RNA) product synthesized by transcription of DNA, and processed to yield various mature RNA products such as mRNAs, tRNAs, and rRNAs. The primary transcripts designated to be mRNAs ...
.
Structure
FUS/TLS is a member of the
FET protein family The FET protein family (also known as the TET protein family consists of three similarly structured and functioning proteins. They and the genes in the FET gene family which encode them (i.e. form the pre-messenger RNAs that are converted to the mes ...
that also includes the
EWS protein, the
TATA-binding protein
The TATA-binding protein (TBP) is a general transcription factor that binds specifically to a DNA sequence called the TATA box. This DNA sequence is found about 30 base pairs upstream of the transcription start site in some eukaryotic gen ...
TBP-associated factor TAFII68/
TAF15
TATA-binding protein-associated factor 2N is a protein that in humans is encoded by the ''TAF15'' gene.
Function
Initiation of transcription by RNA polymerase II requires the activities of more than 70 polypeptides. The protein that coordinates ...
, and the Drosophila cabeza/SARF protein.
FUS/TLS,
EWS and TAF15 have a similar structure, characterised by an
N-terminal
The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
QGSY-rich region, a highly conserved
RNA recognition motif
RNA recognition motif, RNP-1 is a putative RNA-binding domain of about 90 amino acids that are known to bind single-stranded RNAs. It was found in many eukaryotic proteins.
The largest group of single strand RNA-binding protein is the eukaryot ...
(RRM), multiple
R GG repeats, which are extensively
demethylated Demethylation is the chemical process resulting in the removal of a methyl group (CH3) from a molecule. A common way of demethylation is the replacement of a methyl group by a hydrogen atom, resulting in a net loss of one carbon and two hydrogen ato ...
at arginine residues
and a
C-terminal
The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
zinc finger
A zinc finger is a small protein structural motif that is characterized by the coordination of one or more zinc ions (Zn2+) in order to stabilize the fold. It was originally coined to describe the finger-like appearance of a hypothesized struct ...
motif.
Function
The
N-terminal
The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
end of FUS appears to be involved in transcriptional activation, while the
C-terminal
The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
end is involved in protein and RNA binding. In addition recognition sites for the transcription factors
AP2,
GCF,
Sp1 have been identified in FUS.
Consistently, in vitro studies have shown that FUS/TLS binds RNA, single-stranded DNA and (with lower affinity) double-stranded DNA.
The sequence specificity of FUS/TLS binding to RNA or DNA has not been well established; however, using in vitro selection (SELEX), a common GGUG motif has been identified in approximately half of the RNA sequences bound by FUS/TLS.
A later proposal was that the GGUG motif is recognised by the zinc finger domain and not the RRM (80). Additionally, FUS/TLS has been found to bind a relatively long region in the 3′ untranslated region (UTR) of the actin-stabilising protein Nd1-L mRNA, suggesting that rather than recognising specific short sequences, FUS/TLS interacts with multiple RNA-binding motifs or recognises secondary conformations.
FUS/TLS has also been proposed to bind human telomeric RNA (UUAGGG)4 and single-stranded human telomeric DNA in vitro.
Beyond nucleic acid binding, FUS/TLS was also found to associate with both general and more specialized protein factors to influence the initiation of transcription.
Indeed, FUS/TLS interacts with several
nuclear receptor
In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroids, thyroid hormones, vitamins, and certain other molecules. These receptors work with other proteins to regulate the expression of speci ...
s.
and with gene-specific transcription factors such as Spi-1/PU.1.
or
NF-κB
Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular ...
.
It also associates with the general transcriptional machinery and may influence transcription initiation and promoter selection by interacting with RNA polymerase II and the TFIID complex.
Recently, FUS/TLS was also shown to repress the transcription of RNAP III genes and to co-immunoprecipitate with TBP and the TFIIIB complex.
FUS-mediated DNA repair
FUS appears at sites of
DNA damage
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA da ...
very rapidly, which suggests that FUS is orchestrating the
DNA repair
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA dam ...
response.
The function of FUS in the DNA damage response in
neuron
A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...
s involves a direct interaction with histone deacetylase 1 (
HDAC1
Histone deacetylase 1 (HDAC1) is an enzyme that in humans is encoded by the ''HDAC1'' gene.
Function
Histone acetylation and deacetylation, catalyzed by multisubunit complexes, play a key role in the regulation of eukaryotic gene expression. T ...
). The recruitment of FUS to double-strand break sites is important for DNA damage response signaling and for repair of DNA damage.
FUS loss-of-function results in increased DNA damage in neurons. Mutations in the FUS
nuclear localization sequence A nuclear localization signal ''or'' sequence (NLS) is an amino acid sequence that 'tags' a protein for import into the cell nucleus by nuclear transport. Typically, this signal consists of one or more short sequences of positively charged lysines o ...
impairs the
poly (ADP-ribose) polymerase
Poly (ADP-ribose) polymerase (PARP) is a family of proteins involved in a number of cellular processes such as DNA repair, genomic stability, and programmed cell death.
Members of PARP family
The PARP family comprises 17 members (10 putative) ...
(PARP)-dependent DNA damage response.
This impairment leads to neurodegeneration and FUS aggregate formation. Such FUS aggregates are a pathological hallmark of the
neurodegenerative
A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...
disease
amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or Lou Gehrig's disease, is a neurodegenerative disease that results in the progressive loss of motor neurons that control voluntary muscles. ALS is the most comm ...
(ALS).
Clinical significance
FUS gene rearrangement has been implicated in the pathogenesis of
myxoid liposarcoma
A myxoid liposarcoma is a malignant adipose tissue neoplasm of myxoid appearance histologically.
Myxoid liposarcomas are the second-most common type of liposarcoma, representing 30–40% of all liposarcomas in the limbs, occurring most commonly ...
,
low-grade fibromyxoid sarcoma
Low-grade fibromyxoid sarcoma (LGFMS) is a rare type of low-grade sarcoma first described by H. L. Evans in 1987. LGFMS are soft tissue tumors of the mesenchyme-derived connective tissues; on microscopic examination, they are found to be composed ...
,
Ewing sarcoma
Ewing sarcoma is a type of cancer that forms in bone or soft tissue. Symptoms may include swelling and pain at the site of the tumor, fever, and a bone fracture. The most common areas where it begins are the legs, pelvis, and chest wall. In about ...
, and a wide range of other malignant and benign tumors (see
FET protein family The FET protein family (also known as the TET protein family consists of three similarly structured and functioning proteins. They and the genes in the FET gene family which encode them (i.e. form the pre-messenger RNAs that are converted to the mes ...
).
In 2009 two separate research groups analysed 26 unrelated families who presented with a type6
ALS
Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or Lou Gehrig's disease, is a neurodegenerative disease that results in the progressive loss of motor neurons that control voluntary muscles. ALS is the most com ...
phenotype, and found 14 mutations in the ''FUS'' gene.
Subsequently, FUS has also emerged as a significant disease protein in a subgroup of
frontotemporal dementia
Frontotemporal dementia (FTD), or frontotemporal degeneration disease, or frontotemporal neurocognitive disorder, encompasses several types of dementia involving the progressive degeneration of frontal and temporal lobes. FTDs broadly present as ...
s (FTDs), previously characterized by immunoreactivity of the
inclusion bodies
Inclusion bodies are aggregates of specific types of protein found in neurons, a number of tissue cells including red blood cells, bacteria, viruses, and plants. Inclusion bodies of aggregations of multiple proteins are also found in muscle cells ...
for
ubiquitin
Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fo ...
, but not for
TDP-43
TAR DNA-binding protein 43 (TDP-43, transactive response DNA binding protein 43 kDa) is a protein that in humans is encoded by the ''TARDBP'' gene.
Structure
TDP-43 is 414 amino acid residues long. It consists of 4 domains: an N-terminal d ...
or
tau
Tau (uppercase Τ, lowercase τ, or \boldsymbol\tau; el, ταυ ) is the 19th letter of the Greek alphabet, representing the voiceless dental or alveolar plosive . In the system of Greek numerals, it has a value of 300.
The name in English ...
with a proportion of the inclusions also containing
alpha-internexin (α-internexin) in a further subgroup known as
neuronal intermediate filament inclusion disease (NIFID). The disease entities which are now considered subtypes of FTLD-FUS are atypical frontotemporal lobar degeneration with ubiquitinated inclusions (aFTLD-U), NIFID, and
basophilic inclusion body disease (BIBD), which together with ALS-FUS comprise the FUS-proteopathies.
Frontotemporal lobar degeneration
Frontotemporal lobar degeneration (FTLD) is a pathological process that occurs in frontotemporal dementia. It is characterized by atrophy in the frontal lobe and temporal lobe of the brain, with sparing of the parietal and occipital lobes.
Common ...
FTLD) is the pathological term for the clinical syndrome of
frontotemporal dementia
Frontotemporal dementia (FTD), or frontotemporal degeneration disease, or frontotemporal neurocognitive disorder, encompasses several types of dementia involving the progressive degeneration of frontal and temporal lobes. FTDs broadly present as ...
(FTD). FTD differs from the more common
Alzheimer's dementia
Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As t ...
in that memory is relatively well preserved; instead, the disease presents with a more temporal-lobe phenotype.
Behavioral variant frontotemporal dementia (bvFTD),
progressive non-fluent aphasia (PNFA) and
semantic dementia
Semantic dementia (SD), also known as semantic variant primary progressive aphasia (svPPA), is a progressive neurodegenerative disorder characterized by loss of semantic memory in both the verbal and non-verbal domains. However, the most common p ...
(SD) are the three best-characterised clinical presentations. FUS positive FTLD tends to present clinically as a bvFTD but the correlation between underlying pathology and clinical presentation is not perfect.
Toxic mechanism in ALS
The toxic mechanism by which mutant FUS causes ALS is currently unclear. It is known that many of the ALS-linked mutations are located in its C-terminal nuclear localisation signal, resulting in it being located in the cytoplasm rather than the nucleus (where wild-type FUS primarily resides). This suggests either a loss of nuclear function, or a toxic gain of cytoplasmic function, is responsible for the development of this type of ALS. Many researchers believe the toxic gain of cytoplasmic function model to be more likely as mouse models that do not express FUS, and therefore have a complete loss of nuclear FUS function, do not develop clear ALS-like symptoms.
Interactions
FUS has been shown to
interact
Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with:
*
FUSIP1
FUS-interacting serine-arginine-rich protein 1 is a protein that in humans is encoded by the ''SFRS13A'' gene.
Function
This gene product is a member of the serine-arginine ( SR) family of proteins, which is involved in constitutive and regula ...
/SRSF10
*
HDAC1
Histone deacetylase 1 (HDAC1) is an enzyme that in humans is encoded by the ''HDAC1'' gene.
Function
Histone acetylation and deacetylation, catalyzed by multisubunit complexes, play a key role in the regulation of eukaryotic gene expression. T ...
*
ILF3
Interleukin enhancer-binding factor 3 is a protein that in humans is encoded by the ''ILF3'' gene.
Function
Nuclear factor of activated T-cells (NFAT) is a transcription factor required for T-cell expression of interleukin 2. NFAT binds to a s ...
,
*
PRMT1
Protein arginine N-methyltransferase 1 is an enzyme that in humans is encoded by the ''PRMT1'' gene. The HRMT1L2 gene encodes a protein arginine methyltransferase that functions as a histone methyltransferase specific for histone H4.
Function
...
,
*
RELA
Transcription factor p65 also known as nuclear factor NF-kappa-B p65 subunit is a protein that in humans is encoded by the ''RELA'' gene.
RELA, also known as p65, is a REL-associated protein involved in NF-κB heterodimer formation, nuclear tran ...
,
*
RNA polymerase II (C-terminal domain)
*
SPI1
Transcription factor PU.1 is a protein that in humans is encoded by the ''SPI1'' gene.
Function
This gene encodes an ETS-domain transcription factor that activates gene expression during myeloid and B-lymphoid cell development. The nuclear pro ...
,
and
*
TNPO1.
References
Further reading
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