The exosome complex (or PM/Scl complex, often just called the exosome) is a multi-
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 ...
intracellular
complex
Complex commonly refers to:
* Complexity, the behaviour of a system whose components interact in multiple ways so possible interactions are difficult to describe
** Complex system, a system composed of many components which may interact with each ...
capable of degrading various types of
RNA (ribonucleic acid) molecules. Exosome complexes are found in both
eukaryotic
Eukaryotes () are organisms whose Cell (biology), cells have a cell nucleus, nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the ...
cells and
archaea, while in
bacteria
Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of prokaryotic microorganisms. Typically a few micrometr ...
a simpler complex called the
degradosome The degradosome is a multiprotein complex present in most bacteria that is involved in the processing of ribosomal RNA and the degradation of messenger RNA and is regulated by Non-coding RNA. It contains the proteins RNA helicase B, RNase E and ...
carries out similar functions.
The core of the exosome contains a six-membered ring structure to which other proteins are attached. In eukaryotic cells, the exosome complex is present in the
cytoplasm
In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. ...
,
nucleus
Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to:
*Atomic nucleus, the very dense central region of an atom
* Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA
Nucl ...
, and especially the
nucleolus
The nucleolus (, plural: nucleoli ) is the largest structure in the nucleus of eukaryotic cells. It is best known as the site of ribosome biogenesis, which is the synthesis of ribosomes. The nucleolus also participates in the formation of ...
, although different proteins interact with the exosome complex in these compartments regulating the RNA degradation activity of the complex to
substrates specific to these cell compartments. Substrates of the exosome include
messenger RNA,
ribosomal RNA
Ribosomal ribonucleic acid (rRNA) is a type of non-coding RNA which is the primary component of ribosomes, essential to all cells. rRNA is a ribozyme which carries out protein synthesis in ribosomes. Ribosomal RNA is transcribed from ribosom ...
, and many species of
small RNA
Small RNA (sRNA) are polymeric RNA molecules that are less than 200 nucleotides in length, and are usually non-coding. RNA silencing is often a function of these molecules, with the most common and well-studied example being RNA interference (RN ...
s. The exosome has an exoribonucleolytic function, meaning it degrades RNA starting at one end (the
3′ end
Directionality, in molecular biology and biochemistry, is the end-to-end chemical orientation of a single strand of nucleic acid. In a single strand of DNA or RNA, the chemical convention of naming carbon atoms in the nucleotide pentose-sugar-r ...
in this case), and in eukaryotes also an endoribonucleolytic function, meaning it cleaves RNA at sites within the molecule.
Several proteins in the exosome are the target of
autoantibodies in patients with specific
autoimmune diseases (especially the
PM/Scl overlap syndrome) and some
antimetabolic chemotherapies
Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemothera ...
for
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
function by blocking the activity of the exosome. In addition, mutations in
exosome component 3
Exosome component 3, also known as EXOSC3, is a human gene, which is part of the exosome complex.
Clinical significance
Mutations in EXOSC3 cause pontocerebellar hypoplasia
Pontocerebellar hypoplasia (PCH) is a heterogeneous group of rare ...
cause
pontocerebellar hypoplasia
Pontocerebellar hypoplasia (PCH) is a heterogeneous group of rare neurodegenerative disorders caused by genetic mutations and characterised by progressive atrophy of various parts of the brain such as the cerebellum or brainstem (particularly th ...
and spinal
motor neuron disease
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 ...
.
Discovery
The exosome was first discovered as an
RNase
Ribonuclease (commonly abbreviated RNase) is a type of nuclease that catalyzes the degradation of RNA into smaller components. Ribonucleases can be divided into endoribonucleases and exoribonucleases, and comprise several sub-classes within t ...
in 1997 in the budding yeast ''
Saccharomyces cerevisiae
''Saccharomyces cerevisiae'' () (brewer's yeast or baker's yeast) is a species of yeast (single-celled fungus microorganisms). The species has been instrumental in winemaking, baking, and brewing since ancient times. It is believed to have b ...
'', an often-used
model organism.
Not long after, in 1999, it was realized that the exosome was in fact the yeast equivalent of an already described complex in human cells called the ''PM/Scl complex'', which had been identified as an autoantigen in patients with certain
autoimmune diseases years earlier (see
below). Purification of this "PM/Scl complex" allowed the identification of more human exosome proteins and eventually the characterization of all components in the complex. In 2001, the increasing amount of
genome data that had become available allowed the prediction of exosome proteins in archaea, although it would take another 2 years before the first exosome complex from an archaeal organism was purified.
Structure
Core proteins
The core of the complex has a ring structure consisting of six proteins that all belong to the same class of RNases, the
RNase PH-like proteins.
In archaea there are two different PH-like proteins (called Rrp41 and Rrp42), each present three times in an alternating order. Eukaryotic exosome complexes have six different proteins that form the ring structure.
Of these six eukaryotic proteins, three resemble the archaeal Rrp41 protein and the other three proteins are more similar to the archaeal Rrp42 protein.
Located on top of this ring are three proteins that have an S1
RNA binding domain (RBD). Two proteins in addition have a
K-homology (KH) domain.
In eukaryotes, three different "S1" proteins are bound to the ring, whereas in archaea either one or two different "S1" proteins can be part of the exosome (although there are always three S1 subunits attached to the complex).
This ring structure is very similar to that of the proteins
RNase PH and
PNPase. In bacteria, the protein RNase PH, which is involved in
tRNA
Transfer RNA (abbreviated tRNA and formerly referred to as sRNA, for soluble RNA) is an adaptor molecule composed of RNA, typically 76 to 90 nucleotides in length (in eukaryotes), that serves as the physical link between the mRNA and the amino ...
processing, forms a hexameric ring consisting of six identical RNase PH proteins.
In the case of PNPase, which is a phosphorolytic RNA-degrading protein found in
bacteria
Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of prokaryotic microorganisms. Typically a few micrometr ...
and the
chloroplasts
A chloroplast () is a type of membrane-bound organelle known as a plastid that conducts photosynthesis mostly in plant and algal cells. The photosynthetic pigment chlorophyll captures the energy from sunlight, converts it, and stores it in ...
and
mitochondria of some eukaryotic organisms, two RNase PH domains, and both an S1 and KH RNA binding domain are part of a single protein, which forms a trimeric complex that adopts a structure almost identical to that of the exosome. Because of this high similarity in both protein domains and structure, these complexes are thought to be
evolution
Evolution is change in the heritable characteristics of biological populations over successive generations. These characteristics are the expressions of genes, which are passed on from parent to offspring during reproduction. Variation ...
arily related and have a
common ancestor
Common descent is a concept in evolutionary biology applicable when one species is the ancestor of two or more species later in time. All living beings are in fact descendants of a unique ancestor commonly referred to as the last universal comm ...
. The RNase PH-like exosome proteins, PNPase and RNase PH all belong to the RNase PH family of RNases and are phosphorolytic
exoribonuclease
An exoribonuclease is an exonuclease ribonuclease, which are enzymes that degrade RNA by removing terminal nucleotides from either the 5' end or the 3' end of the RNA molecule. Enzymes that remove nucleotides from the 5' end are called ''5'-3 ...
s, meaning that they use
inorganic phosphate
In chemistry, a phosphate is an anion, salt, functional group or ester derived from a phosphoric acid. It most commonly means orthophosphate, a derivative of orthophosphoric acid .
The phosphate or orthophosphate ion is derived from phosph ...
to remove nucleotides from the
3' end
Directionality, in molecular biology and biochemistry, is the end-to-end chemical orientation of a single strand of nucleic acid. In a single strand of DNA or RNA, the chemical convention of naming carbon atoms in the nucleotide pentose-sugar-r ...
of
RNA molecules.
Associated proteins
Besides these nine core exosome proteins, two other proteins often associate with the complex in eukaryotic organisms. One of these is Rrp44, a hydrolytic RNase, which belongs to the
RNase R RNase R, or Ribonuclease R, is a 3'-->5' exoribonuclease, which belongs to the RNase II superfamily, a group of enzymes that hydrolyze RNA in the 3' - 5' direction. RNase R has been shown to be involved in selective mRNA degradation, particularly o ...
family of hydrolytic
exoribonuclease
An exoribonuclease is an exonuclease ribonuclease, which are enzymes that degrade RNA by removing terminal nucleotides from either the 5' end or the 3' end of the RNA molecule. Enzymes that remove nucleotides from the 5' end are called ''5'-3 ...
s (nucleases that use water to cleave the nucleotide bonds). In addition to being an exoribonucleolytic enzyme, Rrp44 also has endoribonucleolytic activity, which resides in a separate domain of the protein. In yeast, Rrp44 is associated with ''all'' exosome complexes and has a crucial role in the activity of the yeast exosome complex. While a human homologue of the protein exists, no evidence was found for a long time that its human homologue was associated with the human exosome complex.
In 2010, however, it was discovered that humans have three Rrp44 homologues and two of these can be associated with the exosome complex. These two proteins most likely degrade different RNA substrates due to their different cellular localization, with one being localized in the cytoplasm (
DIS3L1) and the other in the nucleus (
DIS3
Exosome complex exonuclease RRP44 or Dis3 is an enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts t ...
).
The second common associated protein is called ''Rrp6'' (in yeast) or ''PM/Scl-100'' (in human). Like Rrp44, this protein is a hydrolytic exoribonuclease, but in this case of the
RNase D
Ribonuclease (commonly abbreviated RNase) is a type of nuclease that catalyzes the degradation of RNA into smaller components. Ribonucleases can be divided into endoribonucleases and exoribonucleases, and comprise several sub-classes within t ...
protein family. The protein PM/Scl-100 is most commonly part of exosome complexes in the nucleus of cells, but can form part of the cytoplasmic exosome complex as well.
Regulatory proteins
Apart from these two tightly bound protein subunits, many proteins interact with the exosome complex in both the cytoplasm and nucleus of cells. These loosely associated proteins may regulate the activity and specificity of the exosome complex. In the cytoplasm, the exosome interacts with
AU rich element (ARE) binding proteins (e.g. KRSP and TTP), which can promote or prevent degradation of mRNAs. The nuclear exosome associates with RNA binding proteins (e.g. MPP6/Mpp6 and C1D/Rrp47 in humans/yeast) that are required for processing certain substrates.
In addition to single proteins, other protein complexes interact with the exosome. One of those is the cytoplasmic
Ski complex The Ski complex is a multi-protein complex involved in the 3' end degradation of messenger RNAs in yeast.
Structure
The complex consists of three main proteins, the RNA helicase ''Ski2'' and the proteins ''Ski3'' and ''Ski8''. This tetramer con ...
, which includes an RNA
helicase
Helicases are a class of enzymes thought to be vital to all organisms. Their main function is to unpack an organism's genetic material. Helicases are motor proteins that move directionally along a nucleic acid phosphodiester backbone, separatin ...
(Ski2) and is involved in mRNA degradation. In the nucleus, the processing of rRNA and snoRNA by the exosome is mediated by the
TRAMP complex TRAMP complex (Trf4/Air2/Mtr4p Polyadenylation complex) is a multiprotein, heterotrimeric complex having distributive polyadenylation activity and identifies wide varieties of RNAs produced by polymerases. It was originally discovered in ''Saccharo ...
, which contains both RNA helicase (Mtr4) and
polyadenylation (Trf4) activity.
Function
Enzymatic function
As stated above, the exosome complex contains many proteins with ribonuclease domains. The exact nature of these ribonuclease domains has changed across evolution from bacterial to archaeal to eukaryotic complexes as various activities have been gained and lost. The exosome is primarily a 3'-5'
exoribonuclease
An exoribonuclease is an exonuclease ribonuclease, which are enzymes that degrade RNA by removing terminal nucleotides from either the 5' end or the 3' end of the RNA molecule. Enzymes that remove nucleotides from the 5' end are called ''5'-3 ...
, meaning that it degrades RNA molecules from their
3' end
Directionality, in molecular biology and biochemistry, is the end-to-end chemical orientation of a single strand of nucleic acid. In a single strand of DNA or RNA, the chemical convention of naming carbon atoms in the nucleotide pentose-sugar-r ...
. Exoribonucleases contained in exosome complexes are either phosphorolytic (the RNase PH-like proteins) or, in eukaryotes, hydrolytic (the RNase R and RNase D domain proteins). The phosphorolytic enzymes use inorganic phosphate to cleave the
phosphodiester bond
In chemistry, a phosphodiester bond occurs when exactly two of the hydroxyl groups () in phosphoric acid react with hydroxyl groups on other molecules to form two ester bonds. The "bond" involves this linkage . Discussion of phosphodiesters is d ...
s – releasing
nucleotide diphosphates. The hydrolytic enzymes use water to
hydrolyse
Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile.
Biological hydrolys ...
these bonds – releasing
nucleotide monophosphates.
In archaea, the Rrp41 subunit of the complex is a phosphorolytic exoribonuclease. Three copies of this protein are present in the ring and are responsible for the activity of the complex.
In eukaryotes, none of the RNase PH subunits have retained this catalytic activity, meaning the core ring structure of the human exosome has no enzymatically active protein. Despite this loss of catalytic activity, the structure of the core exosome is highly conserved from archaea to humans, suggesting that the complex performs a vital cellular function. In eukaryotes, the absence of the phosphorolytic activity is compensated by the presence of the hydrolytic enzymes, which are responsible for the ribonuclease activity of the exosome in such organisms.
As stated above, the hydrolytic proteins Rrp6 and Rrp44 are associated with the exosome in yeast and in humans, besides Rrp6, two different proteins, Dis3 and Dis3L1 can be associated at the position of the yeast Rrp44 protein.
Although originally the S1 domain proteins were thought to have 3'-5' hydrolytic exoribonuclease activity as well, the existence of this activity has recently been questioned and these proteins might have just a role in binding substrates prior to their degradation by the complex.
Substrates
The exosome is involved in the degradation and
processing
Processing is a free graphical library and integrated development environment (IDE) built for the electronic arts, new media art, and visual design communities with the purpose of teaching non-programmers the fundamentals of computer programming ...
of a wide variety of RNA species. In the
cytoplasm
In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. ...
of cells, it is involved in the turn-over of
messenger RNA (mRNA) molecules. The complex can degrade mRNA molecules that have been tagged for degradation because they contain errors, through interactions with proteins from the
nonsense mediated decay
Nonsense-mediated mRNA decay (NMD) is a surveillance pathway that exists in all eukaryotes. Its main function is to reduce errors in gene expression by eliminating mRNA transcripts that contain premature stop codons. Translation of these aberran ...
or
non-stop decay
Non-stop decay (NSD) is a cellular mechanism of mRNA surveillance to detect mRNA molecules lacking a stop codon and prevent these mRNAs from translation. The non-stop decay pathway releases ribosomes that have reached the far 3' end of an mRNA and ...
pathways. In alternative fashion, mRNAs are degraded as part of their
normal turnover. Several proteins that stabilize or destabilize mRNA molecules through binding to AU-rich elements in the
3' untranslated region
In molecular genetics, the three prime untranslated region (3′-UTR) is the section of messenger RNA (mRNA) that immediately follows the translation termination codon. The 3′-UTR often contains regulatory regions that post-transcriptionally ...
of mRNAs interact with the exosome complex. In the
nucleus
Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to:
*Atomic nucleus, the very dense central region of an atom
* Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA
Nucl ...
, the exosome is required for the correct processing of several
small nuclear RNA molecules.
Finally, the
nucleolus
The nucleolus (, plural: nucleoli ) is the largest structure in the nucleus of eukaryotic cells. It is best known as the site of ribosome biogenesis, which is the synthesis of ribosomes. The nucleolus also participates in the formation of ...
is the compartment where the majority of the exosome complexes are found. There it plays a role in the processing of the 5.8S
ribosomal RNA
Ribosomal ribonucleic acid (rRNA) is a type of non-coding RNA which is the primary component of ribosomes, essential to all cells. rRNA is a ribozyme which carries out protein synthesis in ribosomes. Ribosomal RNA is transcribed from ribosom ...
(the first identified function of the exosome) and of several
small nucleolar RNAs.
Although most cells have other enzymes that can degrade RNA, either from the
3' or from the
5' end of the RNA, the exosome complex is essential for cell survival. When the
expression
Expression may refer to:
Linguistics
* Expression (linguistics), a word, phrase, or sentence
* Fixed expression, a form of words with a specific meaning
* Idiom, a type of fixed expression
* Metaphorical expression, a particular word, phrase, o ...
of exosome proteins is artificially reduced or stopped, for example by
RNA interference
RNA interference (RNAi) is a biological process in which RNA molecules are involved in sequence-specific suppression of gene expression by double-stranded RNA, through translational or transcriptional repression. Historically, RNAi was known by ...
, growth stops and the cells eventually die. Both the core proteins of the exosome complex, as well as the two main associated proteins, are essential proteins.
Bacteria
Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of prokaryotic microorganisms. Typically a few micrometr ...
do not have an exosome complex; however, similar functions are performed by a simpler complex that includes the protein
PNPase, called the ''
degradosome The degradosome is a multiprotein complex present in most bacteria that is involved in the processing of ribosomal RNA and the degradation of messenger RNA and is regulated by Non-coding RNA. It contains the proteins RNA helicase B, RNase E and ...
''.
The exosome is a key complex in cellular RNA quality control. Unlike prokaryotes, eukaryotes possess highly active RNA surveillance systems that recognise unprocessed and mis-processed RNA-protein complexes (such as
ribosomes
Ribosomes ( ) are macromolecular machines, found within all cells, that perform biological protein synthesis (mRNA translation). Ribosomes link amino acids together in the order specified by the codons of messenger RNA (mRNA) molecules to ...
) prior to their exit from the nucleus. It is presumed that this system prevents aberrant complexes from interfering with important cellular processes such as
protein synthesis.
In addition to RNA processing, turnover and surveillance activities, the exosome is important for the degradation of so-called
cryptic unstable transcript Cryptic unstable transcripts (CUTs) are a subset of non-coding RNAs (ncRNAs) that are produced from intergenic and intragenic regions. CUTs were first observed in ''S. cerevisiae'' yeast models and are found in most eukaryotes. Some basic characte ...
s (CUTs) that are produced from thousands of loci within the yeast genome. The importance of these unstable RNAs and their degradation are still unclear, but similar RNA species have also been detected in human cells.
Disease
Autoimmunity
The exosome complex is the target of
autoantibodies in patients with various
autoimmune diseases. These autoantibodies are mainly found in people with the
PM/Scl overlap syndrome, an autoimmune disease in which patients have symptoms from both
scleroderma
Scleroderma is a group of autoimmune diseases that may result in changes to the skin, blood vessels, muscles, and internal organs. The disease can be either localized to the skin or involve other organs, as well. Symptoms may include areas ...
and either
polymyositis
Polymyositis (PM) is a type of chronic inflammation of the muscles (inflammatory myopathy) related to dermatomyositis and inclusion body myositis. Its name means "inflammation of many muscles" ('' poly-'' + '' myos-'' + '' -itis''). The inflam ...
or
dermatomyositis
Dermatomyositis (DM) is a long-term inflammatory disorder which affects skin and the muscles. Its symptoms are generally a skin rash and worsening muscle weakness over time. These may occur suddenly or develop over months. Other symptoms may inc ...
. Autoantibodies can be detected in the
serum of patients by a variety of assays. In the past, the most commonly used methods were
double immunodiffusion using calf
thymus
The thymus is a specialized primary lymphoid organ of the immune system. Within the thymus, thymus cell lymphocytes or ''T cells'' mature. T cells are critical to the adaptive immune system, where the body adapts to specific foreign invaders. ...
extracts,
immunofluorescence on HEp-2 cells or
immunoprecipitation from human cell extracts. In immunoprecipitation assays with sera from anti-exosome positive sera, a distinctive set of proteins is precipitated. Already years before the exosome complex was identified, this pattern was termed the ''PM/Scl complex''. Immunofluorescence using sera from these patients usually shows a typical staining of the
nucleolus
The nucleolus (, plural: nucleoli ) is the largest structure in the nucleus of eukaryotic cells. It is best known as the site of ribosome biogenesis, which is the synthesis of ribosomes. The nucleolus also participates in the formation of ...
of cells, which sparked the suggestion that the antigen recognized by autoantibodies might be important in ribosome
synthesis. More recently,
recombinant exosome proteins have become available and these have been used to develop line immunoassays (LIAs) and
enzyme linked immunosorbent assays (ELISAs) for detecting these antibodies.
In these diseases, antibodies are mainly directed against two of the proteins of the complex, called ''PM/Scl-100'' (the RNase D like protein) and ''PM/Scl-75'' (one of the RNase PH like proteins from the ring) and antibodies recognizing these proteins are found in approximately 30% of patients with the PM/Scl overlap syndrome. Although these two proteins are the main target of the autoantibodies, other exosome subunits and associated proteins (like C1D) can be targeted in these patients. At the current time, the most sensitive way to detect these antibodies is by using a
peptide
Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides.
...
, derived from the PM/Scl-100 protein, as the antigen in an
ELISA
The enzyme-linked immunosorbent assay (ELISA) (, ) is a commonly used analytical biochemistry assay, first described by Eva Engvall and Peter Perlmann in 1971. The assay uses a solid-phase type of enzyme immunoassay (EIA) to detect the presen ...
, instead of complete proteins. By this method, autoantibodies are found in up to 55% of patients with the PM/Scl overlap syndrome, but they can also be detected in patients with either scleroderma, polymyositis, or dermatomyositis alone.
As the autobodies are found mainly in patients that have characteristics of several different autoimmune diseases, the
clinical symptom
Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. A sign for example may be a higher or lower temperature than normal, raised or lowered blood pressure or an abnormality showin ...
s of these patients can vary widely. The symptoms that are seen most often are the typical symptoms of the individual autoimmune diseases and include
Raynaud's phenomenon
Raynaud syndrome, also known as Raynaud's phenomenon, eponymously named after the physician Auguste Gabriel Maurice Raynaud, who first described it in his doctoral thesis in 1862, is a medical condition in which the spasm of small arteries cau ...
,
arthritis,
myositis
Myositis is a rare disease that involves inflammation of the muscles. This can present with a variety of symptoms such as skin involvement (i.e., rashes), muscle weakness, and other organ involvement. Systemic symptoms such as weight loss, fatigue ...
and
scleroderma
Scleroderma is a group of autoimmune diseases that may result in changes to the skin, blood vessels, muscles, and internal organs. The disease can be either localized to the skin or involve other organs, as well. Symptoms may include areas ...
. Treatment of these patients is symptomatic and is similar to treatment for the individual autoimmune disease, often involving either
immunosuppressive
Immunosuppression is a reduction of the activation or efficacy of the immune system. Some portions of the immune system itself have immunosuppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse reacti ...
or immunomodulating drugs.
Cancer treatment
The exosome has been shown to be inhibited by the
antimetabolite
An antimetabolite is a chemical that inhibits the use of a metabolite, which is another chemical that is part of normal metabolism. Such substances are often similar in structure to the metabolite that they interfere with, such as the antifolate ...
fluorouracil
Fluorouracil (5-FU), sold under the brand name Adrucil among others, is a cytotoxic chemotherapy medication used to treat cancer. By intravenous injection it is used for treatment of colorectal cancer, oesophageal cancer, stomach cancer, pan ...
, a drug used in the
chemotherapy
Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs ( chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemothe ...
of
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
. It is one of the most successful drugs for treating solid
tumor
A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
s. In yeast cells treated with fluorouracil, defects were found in the processing of ribosomal RNA identical to those seen when the activity of the exosome was blocked by
molecular biological
Molecular biology is the branch of biology that seeks to understand the molecular basis of biological activity in and between cells, including biomolecular synthesis, modification, mechanisms, and interactions. The study of chemical and physi ...
strategies. Lack of correct ribosomal RNA processing is lethal to cells, explaining the antimetabolic effect of the drug.
Neurological disorders
Mutations in
exosome component 3
Exosome component 3, also known as EXOSC3, is a human gene, which is part of the exosome complex.
Clinical significance
Mutations in EXOSC3 cause pontocerebellar hypoplasia
Pontocerebellar hypoplasia (PCH) is a heterogeneous group of rare ...
cause infantile spinal
motor neuron disease
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 ...
, cerebellar atrophy, progressive microcephaly and profound global developmental delay, consistent with
pontocerebellar hypoplasia
Pontocerebellar hypoplasia (PCH) is a heterogeneous group of rare neurodegenerative disorders caused by genetic mutations and characterised by progressive atrophy of various parts of the brain such as the cerebellum or brainstem (particularly th ...
type 1B
PCH1B; MIM 614678.
List of subunits
*In archaea several exosome proteins are present in multiple copies, to form the full core of the exosome complex.
*In humans, two different proteins can be associated in this position. In the cytoplasm of cells, Dis3L1 is associated with the exosome, whereas in the nucleus, Dis3 can bind to the core complex.
*Contributes to the ribonucleolytic activity of the complex.
See also
* The
proteasome, the main protein degrading machinery of cells
* The
spliceosome
A spliceosome is a large ribonucleoprotein (RNP) complex found primarily within the nucleus of eukaryotic cells. The spliceosome is assembled from small nuclear RNAs ( snRNA) and numerous proteins. Small nuclear RNA (snRNA) molecules bind to specif ...
, a complex involved in
RNA splicing, that also contains an RNA binding ring structure
References
Further reading
*
*
*
*
*
*
External links
Structure of the human exosome at the RCSB Protein Data BankStructure of an archaeal exosome at the RCSB Protein Data BankStructure of an archaeal exosome bound to RNA at the RCSB Protein Data BankStructure of the yeast exosome protein Rrp6 at the RCSB Protein Data Bank3D macromolecular structures of exosomes at the EM Data Bank(EMDB)
{{DEFAULTSORT:Exosome Complex
Nucleic acids
RNA
Ribonucleases
Protein complexes