Exosome complex
Encyclopedia
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
complex
Protein complex
A multiprotein complex is a group of two or more associated polypeptide chains. If the different polypeptide chains contain different protein domain, the resulting multiprotein complex can have multiple catalytic functions...
capable of degrading various types of RNA
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
(ribonucleic acid) molecules. Exosome complexes are found in both eukaryotic cells and archaea
Archaea
The Archaea are a group of single-celled microorganisms. A single individual or species from this domain is called an archaeon...
, while in bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
a simpler complex called the degradosome
Degradosome
The degradosome is a multi-protein complex present in most bacteria that is involved in the processing of ribosomal RNA and the degradation of messenger RNA. It contains the proteins RNA helicase B, RNase E and Polynucleotide phosphorylase....
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
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
, nucleus
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
and especially the nucleolus
Nucleolus
The nucleolus is a non-membrane bound structure composed of proteins and nucleic acids found within the nucleus. Ribosomal RNA is transcribed and assembled within the nucleolus...
, although different proteins interact with the exosome complex in these compartments regulating the RNA degradation activity of the complex to substrate
Substrate (biochemistry)
In biochemistry, a substrate is a molecule upon which an enzyme acts. Enzymes catalyze chemical reactions involving the substrate. In the case of a single substrate, the substrate binds with the enzyme active site, and an enzyme-substrate complex is formed. The substrate is transformed into one or...
s specific to these cell compartments. Substrates of the exosome include messenger RNA
Messenger RNA
Messenger RNA is a molecule of RNA encoding a chemical "blueprint" for a protein product. mRNA is transcribed from a DNA template, and carries coding information to the sites of protein synthesis: the ribosomes. Here, the nucleic acid polymer is translated into a polymer of amino acids: a protein...
, ribosomal RNA
Ribosomal RNA
Ribosomal ribonucleic acid is the RNA component of the ribosome, the enzyme that is the site of protein synthesis in all living cells. Ribosomal RNA provides a mechanism for decoding mRNA into amino acids and interacts with tRNAs during translation by providing peptidyl transferase activity...
, and many species of small RNAs. The exosome has an exoribonucleolytic function, meaning it degrades RNA starting at one end (the so-called 3′ end in this case), and in eukaryotes also an endoribonucleolytic function, meaning it cleaves RNA at sites within the molecule.
Although no causative relation between the exosome complex and any disease is known, several proteins in the exosome are the target of autoantibodies in patients with specific autoimmune diseases (especially the PM/Scl overlap syndrome
Scleromyositis
Scleromyositis or the PM/Scl overlap syndrome is a complex autoimmune disease . Patients with scleromyositis have symptoms of both systemic scleroderma and either polymyositis or dermatomyositis, and is therefore considered an overlap syndrome...
) and some antimetabolitic
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 antifolates that interfere with the use of folic acid...
chemotherapies for cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
function by blocking the activity of the exosome.
Discovery
The exosome was first discovered as an RNase in 1997 in the budding yeast Saccharomyces cerevisiaeSaccharomyces cerevisiae
Saccharomyces cerevisiae is a species of yeast. It is perhaps the most useful yeast, having been instrumental to baking and brewing since ancient times. It is believed that it was originally isolated from the skin of grapes...
, an often-used model organism
Model organism
A model organism is a non-human species that is extensively studied to understand particular biological phenomena, with the expectation that discoveries made in the organism model will provide insight into the workings of other organisms. Model organisms are in vivo models and are widely used to...
. 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, the so-called PM/Scl complex, which had been identified as an autoantigen in patients with certain autoimmune disease
Autoimmune disease
Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. In other words, the body actually attacks its own cells. The immune system mistakes some part of the body as a pathogen and attacks it. This may be restricted to...
s 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
Genome project
Genome projects are scientific endeavours that ultimately aim to determine the complete genome sequence of an organism and to annotate protein-coding genes and other important genome-encoded features...
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.
Core proteins
RNase PH
RNase PH is an 3'-5' exoribonuclease and nucleotidyltransferase, present in archaea and bacteria, that is involved in tRNA processing. Contrary to hydrolytic enzymes, it is a phosphorolytic enzyme, meaning that it uses inorganic phosphate as a cofactor to cleave nucleotide-nucleotide bonds,...
-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
RNA-binding protein
RNA-binding proteins are proteins that bind to RNA. They bind to either double-strand or single-strand RNAs through RNA recognition motif . RNA-binding proteins may regulate the translation of RNA, and post-transcriptional events, such as RNA splicing, editing.They are cytoplasmic and nuclear...
domain (RBD). Two proteins in addition have a K-homology (KH) domain
KH domain
The K Homology domain is a protein domain that was first identified in the human heterogeneous nuclear ribonucleoprotein K. An evolutionarily conserved sequence of around 70 amino acids, the KH domain is present in a wide variety of nucleic acid-binding proteins. The KH domain binds RNA, and can...
. 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).
RNase PH
RNase PH is an 3'-5' exoribonuclease and nucleotidyltransferase, present in archaea and bacteria, that is involved in tRNA processing. Contrary to hydrolytic enzymes, it is a phosphorolytic enzyme, meaning that it uses inorganic phosphate as a cofactor to cleave nucleotide-nucleotide bonds,...
and PNPase. In bacteria, the protein RNase PH, which is involved in tRNA 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
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
and the chloroplasts 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
Evolution is any change across successive generations in the heritable characteristics of biological populations. Evolutionary processes give rise to diversity at every level of biological organisation, including species, individual organisms and molecules such as DNA and proteins.Life on Earth...
arily related and have a common ancestor. In bacteria, a separate RNase PH protein exists that is involved in transfer RNA
Transfer RNA
Transfer RNA is an adaptor molecule composed of RNA, typically 73 to 93 nucleotides in length, that is used in biology to bridge the three-letter genetic code in messenger RNA with the twenty-letter code of amino acids in proteins. The role of tRNA as an adaptor is best understood by...
processing, which has been shown to adopt a similar six-membered ring structure, but in this case consisting of 6 identical protein subunits. The RNase PH-like exosome proteins, PNPase and RNase PH all belong to the RNase PH family of RNases and are phosphorolytic exoribonuclease
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...
s, meaning that they use inorganic phosphate to remove nucleotides from the 3' end of RNA
RNA
Ribonucleic acid , or RNA, is one of the three major macromolecules that are essential for all known forms of life....
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 RRNase R
RNase R is an 3'-5' exoribonuclease closely related to RNase II, which has been shown to be involved in mRNA degradation in bacteria. RNase R has homologues in many other organisms. When a part of another larger protein has a domain that is very similar to RNase R, this is called an RNase R domain....
family of hydrolytic exoribonuclease
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...
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).
RNase D
RNase D is one of the seven exoribonucleases identified in E. coli. It is an 3'-5' exoribonuclease and which has been shown to be involved in the 3' processing of various stable RNA molecules ; It is known to add the 3' CCA sequence to tRNA in prokaryotic tRNA processing. RNase D has homologues...
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 elementThree prime untranslated region
In molecular genetics, the three prime untranslated region is a particular section of messenger RNA . It is preceeded by the coding region....
(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
Ski complex
The Ski complex is a multi-protein complex involved in the 3' end degradation of messenger RNAs. The complex consists of three main proteins, the RNA helicase Ski2 and the proteins Ski3 and Ski8. In yeast, the complex guides RNA molecules to the exosome complex for degradation via a fourth protein,...
, which includes an RNA helicase
Helicase
Helicases are a class of enzymes vital to all living organisms. They are motor proteins that move directionally along a nucleic acid phosphodiester backbone, separating two annealed nucleic acid strands using energy derived from ATP hydrolysis.-Function:Many cellular processes Helicases are a...
(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
The TRAMP complex is a multi-protein complex consisting of the RNA helicase Mtr4, a poly polymerase and a zinc knuckle protein...
, which contains both RNA helicase (Mtr4) and polyadenylation
Polyadenylation
Polyadenylation is the addition of a poly tail to an RNA molecule. The poly tail consists of multiple adenosine monophosphates; in other words, it is a stretch of RNA that has only adenine bases. In eukaryotes, polyadenylation is part of the process that produces mature messenger RNA for translation...
(Trf4) activity.
Enzymatic function
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...
, meaning that it degrades RNA molecules from their 3' end. 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
Phosphodiester bond
A phosphodiester bond is a group of strong covalent bonds between a phosphate group and two 5-carbon ring carbohydrates over two ester bonds. Phosphodiester bonds are central to all known life, as they make up the backbone of each helical strand of DNA...
s - releasing nucleotide diphosphates
Adenosine diphosphate
Adenosine diphosphate, abbreviated ADP, is a nucleoside diphosphate. It is an ester of pyrophosphoric acid with the nucleoside adenosine. ADP consists of the pyrophosphate group, the pentose sugar ribose, and the nucleobase adenine....
. The hydrolytic enzymes use water to hydrolyse
Hydrolysis
Hydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...
these bonds - releasing nucleotide monophosphates
Adenosine monophosphate
Adenosine monophosphate , also known as 5'-adenylic acid, is a nucleotide that is used as a monomer in RNA. It is an ester of phosphoric acid and the nucleoside adenosine. AMP consists of a phosphate group, the sugar ribose, and the nucleobase adenine...
.
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 archea 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 processingPost-transcriptional modification
Post-transcriptional modification is a process in cell biology by which, in eukaryotic cells, primary transcript RNA is converted into mature RNA. A notable example is the conversion of precursor messenger RNA into mature messenger RNA , which includes splicing and occurs prior to protein synthesis...
of a wide variety of RNA species. In the cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
of cells, it is involved in the turn-over of messenger RNA
Messenger RNA
Messenger RNA is a molecule of RNA encoding a chemical "blueprint" for a protein product. mRNA is transcribed from a DNA template, and carries coding information to the sites of protein synthesis: the ribosomes. Here, the nucleic acid polymer is translated into a polymer of amino acids: a protein...
(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 decay
Nonsense-mediated decay is a cellular mechanism of mRNA surveillance that functions to detect nonsense mutations and prevent the expression of truncated or erroneous proteins. Following transcription, precursor mRNA undergoes an assemblage of ribonucleoprotein components followed by regulatory...
or non-stop decay
Non-stop decay
Non-stop decay 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 guides the mRNA to the exosome complex for degradation. -...
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 of mRNAs interact with the exosome complex. In the nucleus
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
, the exosome is required for the correct processing of several small nuclear RNA molecules. Finally, the nucleolus
Nucleolus
The nucleolus is a non-membrane bound structure composed of proteins and nucleic acids found within the nucleus. Ribosomal RNA is transcribed and assembled within the nucleolus...
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 RNA
Ribosomal ribonucleic acid is the RNA component of the ribosome, the enzyme that is the site of protein synthesis in all living cells. Ribosomal RNA provides a mechanism for decoding mRNA into amino acids and interacts with tRNAs during translation by providing peptidyl transferase activity...
(the first identified function of the exosome) and of several small nucleolar RNAs
SnoRNA
Small nucleolar RNAs are a class of small RNA molecules that primarily guide chemical modifications of other RNAs, mainly ribosomal RNAs, transfer RNAs and small nuclear 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
Protein expression
Protein expression is a subcomponent of gene expression. It consists of the stages after DNA has been translated into polypeptide chains, which are ultimately folded into proteins...
of exosome proteins is artificially reduced or stopped, for example by RNA interference
RNA interference
RNA interference is a process within living cells that moderates the activity of their genes. Historically, it was known by other names, including co-suppression, post transcriptional gene silencing , and quelling. Only after these apparently unrelated processes were fully understood did it become...
, 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
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
do not have an exosome complex; however, similar functions are performed by a simpler complex that includes the protein PNPase
Polynucleotide phosphorylase
Polynucleotide Phosphorylase is a bifunctional enzyme with a phosphorolytic 3' to 5' exoribonuclease activity and a 3'-terminal oligonucleotide polymerase activity. It is involved on mRNA processing and degradation in bacteria, plants, and in humans.In humans, the enzyme is encoded by the gene...
, called the degradosome
Degradosome
The degradosome is a multi-protein complex present in most bacteria that is involved in the processing of ribosomal RNA and the degradation of messenger RNA. It contains the proteins RNA helicase B, RNase E and Polynucleotide phosphorylase....
.
In addition to RNA processing, turnover and surveillance activities, the exosome is important for the degradation of so-called cryptic unstable transcript
Cryptic unstable transcript
Cryptic Unstable Transcripts are a subset of non-coding RNAs that are produced between intergenic and intragenic regions first observed in S. Cerevisiae yeast models and found in most eukaryotes. CUTs belong to a class of RNA molecules transcribed by RNA Polymerase II, but are quickly degraded...
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.
Autoimmunity
The exosome complex is the target of autoantibodies in patients that suffer from various autoimmune diseaseAutoimmune disease
Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. In other words, the body actually attacks its own cells. The immune system mistakes some part of the body as a pathogen and attacks it. This may be restricted to...
s. These autoantibodies are mainly found in people that suffer from the PM/Scl overlap syndrome, an autoimmune disease in which patients have symptoms from both scleroderma
Scleroderma
Systemic sclerosis or systemic scleroderma is a systemic autoimmune disease or systemic connective tissue disease that is a subtype of scleroderma.-Skin symptoms:...
and either polymyositis
Polymyositis
Polymyositis is a type of chronic inflammation of the muscles related to dermatomyositis and inclusion body myositis.-Signs and symptoms:...
or dermatomyositis
Dermatomyositis
Dermatomyositis is a connective-tissue disease related to polymyositis and Bramaticosis that is characterized by inflammation of the muscles and the skin.- Causes :...
. Autoantibodies can be detected in the serum
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
of patients by a variety of assays. In the past, the most commonly used methods were double immunodiffusion
Ouchterlony Double Immuno Diffusion
Ouchterlony double immunodiffusion is a simple, rather dated method which is still considered to be the gold standard for detection of extractable nuclear antigens...
using calf thymus
Thymus
The thymus is a specialized organ of the immune system. The thymus produces and "educates" T-lymphocytes , which are critical cells of the adaptive immune system....
extracts, immunofluorescence
Immunofluorescence
Immunofluorescence is a technique used for light microscopy with a fluorescence microscope and is used primarily on biological samples. This technique uses the specificity of antibodies to their antigen to target fluorescent dyes to specific biomolecule targets within a cell, and therefore allows...
on HEp-2 cells or immunoprecipitation
Immunoprecipitation
Immunoprecipitation is the technique of precipitating a protein antigen out of solution using an antibody that specifically binds to that particular protein. This process can be used to isolate and concentrate a particular protein from a sample containing many thousands of different proteins...
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
Nucleolus
The nucleolus is a non-membrane bound structure composed of proteins and nucleic acids found within the nucleus. Ribosomal RNA is transcribed and assembled within the nucleolus...
of cells, which sparked the suggestion that the antigen recognized by autoantibodies might be important in ribosome synthesis
Biosynthesis
Biosynthesis is an enzyme-catalyzed process in cells of living organisms by which substrates are converted to more complex products. The biosynthesis process often consists of several enzymatic steps in which the product of one step is used as substrate in the following step...
. 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
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
, derived from the PM/Scl-100 protein, as the antigen in an ELISA
ELISA
Enzyme-linked immunosorbent assay , is a popular format of a "wet-lab" type analytic biochemistry assay that uses one sub-type of heterogeneous, solid-phase enzyme immunoassay to detect the presence of a substance in a liquid sample."Wet lab" analytic biochemistry assays involves detection of an...
, 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 suffering from either scleroderma, polymyositis, or dermatomyositis alone.
As the autobodies are found mainly in patients that have characteristics of several different autoimmune diseases, the clinical symptoms 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's phenomenon
In medicine, Raynaud's phenomenon is a vasospastic disorder causing discoloration of the fingers, toes, and occasionally other areas. This condition can also cause nails to become brittle with longitudinal ridges. Named for French physician Maurice Raynaud , the phenomenon is believed to be the...
, arthritis
Arthritis
Arthritis is a form of joint disorder that involves inflammation of one or more joints....
, myositis
Myositis
Myositis is a general term for inflammation of the muscles. Many such conditions are considered likely to be caused by autoimmune conditions, rather than directly due to infection It is also a documented side effect of the lipid-lowering drugs statins and fibrates.Elevation of creatine kinase in...
and scleroderma
Scleroderma
Systemic sclerosis or systemic scleroderma is a systemic autoimmune disease or systemic connective tissue disease that is a subtype of scleroderma.-Skin symptoms:...
. Treatment of these patients is symptomatic and is similar to treatment for the individual autoimmune disease, often involving either immunosuppressive
Immunosuppressive drug
Immunosuppressive drugs or immunosuppressive agents are drugs that inhibit or prevent activity of the immune system. They are used in immunosuppressive therapy to:...
or immunomodulating drugs.
Cancer treatment
The exosome has been shown to be inhibited by the antimetaboliteAntimetabolite
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 antifolates that interfere with the use of folic acid...
fluorouracil
Fluorouracil
Fluorouracil is a drug that is a pyrimidine analog which is used in the treatment of cancer. It is a suicide inhibitor and works through irreversible inhibition of thymidylate synthase. It belongs to the family of drugs called antimetabolites...
, a drug used in the chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
of cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
. It is one of the most successful drugs for treating solid tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
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
Molecular biology is the branch of biology that deals with the molecular basis of biological activity. This field overlaps with other areas of biology and chemistry, particularly genetics and biochemistry...
strategies. Lack of correct ribosomal RNA processing is lethal to cells, explaining the antimetabolic effect of the drug.
List of subunits
| Legend | General name | Domains | Human | Yeast (S. cerevisiae) | Archaea | MW (kD) | Human gene Human Genome Organisation The Human Genome Organisation is an organization involved in the Human Genome Project, a project about mapping the human genome. HUGO was established in 1989 as an international organization, primarily to foster collaboration between genome scientists around the world... |
Yeast gene |
|---|---|---|---|---|---|---|---|---|
| 1 | Csl4 | S1 RBD | hCsl4 | Csl4p/Ski4p | Csl4 | 21-32 | EXOSC1 | |
| 2 | Rrp4 | S1/KH RBD | hRrp4 | Rrp4p | Rrp4 | 28-39 | EXOSC2 Exosome component 2 Exosome component 2, also known as EXOSC2, is a protein which in humans is encoded by the EXOSC2 gene.- Function :Mammalian mRNAs contain AU-rich elements within their three prime untranslated regions. In yeast, 3-prime-to-5-prime mRNA degradation is mediated by the exosome, a multisubunit particle... |
|
| 3 | Rrp40 | S1/KH RBD | hRrp40 | Rrp40p | (Rrp4) | 27-32 | EXOSC3 Exosome component 3 Exosome component 3, also known as EXOSC3, is a human gene, which is part of the exosome complex.-Further reading:... |
|
| 4 | Rrp41 | RNase PH | hRrp41 | Rrp41p/Ski6p | Rrp41 | 26-28 | EXOSC4 | |
| 5 | Rrp46 | RNase PH | hRrp46 | Rrp46p | (Rrp41) | 25-28 | EXOSC5 | |
| 6 | Mtr3 | RNase PH | hMtr3 | Mtr3p | (Rrp41) | 24-37 | EXOSC6 | |
| 7 | Rrp42 | RNase PH | hRrp42 | Rrp42p | Rrp42 | 29-32 | EXOSC7 Exosome component 7 Exosome component 7, also known as EXOSC7, is a human gene, the protein product of which is part of the exosome complex.-Interactions:... |
|
| 8 | Rrp43 | RNase PH | OIP2 | Rrp43p | (Rrp42) | 30-44 | EXOSC8 Exosome component 8 Exosome component 8, also known as EXOSC8, is a human gene, the protein product of which is part of the exosome complex.-Interactions:Exosome component 8 has been shown to interact with Exosome component 5 and Exosome component 6.-Further reading:... |
|
| 9 | Rrp45 | RNase PH | PM/Scl-75 | Rrp45p | (Rrp42) | 34-49 | EXOSC9 Exosome component 9 Exosome component 9, also known as EXOSC9, is a human gene, the protein product of which is part of the exosome complex and is an autoantigen is patients with certain auto immune diseases, most notably scleromyositis.-Further reading:... |
|
| 10 | Rrp6 | RNase D | PM/Scl-100 | Rrp6p | n/a | 84-100 | EXOSC10 | |
| 11 | Rrp44 | RNase R | Dis3 Dis3L1 |
Rrp44p/Dis3p | n/a | 105-113 | DIS3 DIS3 Exosome complex exonuclease RRP44 or Dis3 is an enzyme that in humans is encoded by the DIS3 gene. Its protein product is an RNase enzyme homologous to the yeast protein Rrp44, and can be part of the exosome complex in the nucleus of eukaryotic cells.... DIS3L1 |
See also
- The proteasomeProteasomeProteasomes are very large protein complexes inside all eukaryotes and archaea, and in some bacteria. In eukaryotes, they are located in the nucleus and the cytoplasm. The main function of the proteasome is to degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks...
, the main protein degrading machinery of cells - The spliceosomeSpliceosomeA spliceosome is a complex of snRNA and protein subunits that removes introns from a transcribed pre-mRNA segment. This process is generally referred to as splicing.-Composition:...
, a complex involved in RNA splicingRNA splicingIn molecular biology and genetics, splicing is a modification of an RNA after transcription, in which introns are removed and exons are joined. This is needed for the typical eukaryotic messenger RNA before it can be used to produce a correct protein through translation...
, that also contains an RNA binding ring structure