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<title>Exosome complex</title>
<authors>Wikipedia</authors>
<publisher>wikipedia.org</publisher>
<publishedplace>network</publishedplace>
<publishedyear>2010</publishedyear>
<edition></edition>
<category>Ribonucleases</category>
<section id="41741" fatherid="0" title="" lv="" priority="-1" level="1">
The exosome complex (or PM/Scl complex, often just called the exosome) is a multi-protein complex capable of degrading various types of RNA (ribonucleic acid) molecules. Exosome complexes are found in both eukaryotic cells and archaea, while in bacteria a simpler complex called the degradosome 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, nucleus and especially the nucleolus, 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, 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), rather than cleaving the RNA at specific 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) and some antimetabolitic chemotherapies for cancer function by blocking the activity of the exosome.

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<section id="41742" fatherid="0" title="Discovery" lv="" priority="-2" level="1">
The exosome was first discovered as an RNase in 1997 in the budding yeast Saccharomyces cerevisiae, 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, the so-called 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.
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<section id="41743" fatherid="0" title="Structure" lv="" priority="3" level="1">
<section id="41744" fatherid="41743" title="Core proteins" lv="" priority="1" level="2">
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 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 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 evolutionarily related and have a common ancestor. In bacteria, a separate RNase PH protein exists that is involved in transfer RNA 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 exoribonucleases, meaning they use inorganic phosphate to remove nucleotides from the 3' end of RNA molecules.

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<section id="41745" fatherid="41743" title="Associated proteins" lv="" priority="2" level="2">
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 family of hydrolytic exoribonucleases (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. Remarkably, while a human homologue of the protein exists, no evidence has been found to date that its human homologue is even associated with the human exosome complex.
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<section id="41746" fatherid="41743" title="Regulatory proteins" lv="" priority="3" level="2">
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, which includes an RNA helicase (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, which contains both RNA helicase (Mtr4) and polyadenylation (Trf4) activity.

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<section id="41747" fatherid="0" title="Function" lv="" priority="4" level="1">
<section id="41748" fatherid="41747" title="Enzymatic function" lv="" priority="1" level="2">
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 archeal to eukaryotic complexes as various activities have been gained and lost. The exosome is primarily a 3'-5' exoribonuclease, 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 bonds - releasing nucleotide disphosphates. The hydrolytic enzymes use water to hydrolyse these bonds - releasing nucleotide monosphosphates).
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 protein Rrp44 is associated with the exosome in yeast and in both human and yeast, the hydrolytic enzyme Rrp6 can be associated with the complex. Rrp6 contributes to the activity of the yeast exosome and is solely responsible for the activity of the human complex. 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.

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<section id="41749" fatherid="41747" title="Substrates" lv="" priority="-2" level="2">
The exosome is involved in the degradation and processing of a wide variety of RNA species. In the cytoplasm 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 or non-stop decay pathways. Alternatively, 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, the exosome is required for the correct processing of several small nuclear RNA molecules. Finally, 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 (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 5' end of the RNA, the exosome complex is essential for cell survival. When the expression of exosome proteins is artificially reduced or stopped, for example by RNA interference, 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 do not have an exosome complex; however, similar functions are performed by a simpler complex that includes the protein PNPase, called the degradosome.
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) prior to their exit from the nucleus. This system presumably 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 transcripts (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.

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</section>
<section id="41750" fatherid="0" title="Disease" lv="" priority="5" level="1">
<section id="41751" fatherid="41750" title="Autoimmunity" lv="" priority="-1" level="2">
The exosome complex is the target of autoantibodies in patients that suffer from various autoimmune diseases. 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 and either polymyositis or dermatomyositis. 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 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 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. Currently, the most sensitive way to detect these antibodies is by using a peptide, derived from the PM/Scl-100 protein, as the antigen in an ELISA, 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 mainly found 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, arthritis, myositis and scleroderma. Treatment of these patients is symptomatic and is similar to treatment for the individual autoimmune disease, often involving either immunosuppressive or immunomodulating drugs.

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<section id="41752" fatherid="41750" title="Cancer treatment" lv="" priority="2" level="2">
The exosome has been shown to be inhibited by the antimetabolite fluorouracil, a drug used in the chemotherapy of cancer. It is one of the most successful drugs for treating solid tumors. 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 strategies. Lack of correct ribosomal RNA processing is lethal to cells, explaining the antimetabolic effect of the drug.
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<section id="41753" fatherid="0" title="List of subunits" lv="" priority="-6" level="1">
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<section id="41754" fatherid="0" title="See also" lv="" priority="-7" level="1">
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<section id="41755" fatherid="0" title="References" lv="" priority="-8" level="1">
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<section id="41756" fatherid="0" title="Further reading" lv="" priority="-9" level="1">
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<section id="41757" fatherid="0" title="External links" lv="" priority="-10" level="1">
Category:Nucleic acids
Category:RNA
Category:Ribonucleases
Category:Protein complexes

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