Exosome complex
Protein complex that degrades RNA
title: "Exosome complex" type: doc version: 1 created: 2026-02-28 author: "Wikipedia contributors" status: active scope: public tags: ["nucleic-acids", "rna", "ribonucleases", "protein-complexes"] description: "Protein complex that degrades RNA" topic_path: "politics" source: "https://en.wikipedia.org/wiki/Exosome_complex" license: "CC BY-SA 4.0" wikipedia_page_id: 0 wikipedia_revision_id: 0
::summary Protein complex that degrades RNA ::
::figure[src="https://upload.wikimedia.org/wikipedia/commons/d/d0/Exosome_ribbon.png" caption="legend]] below. The channel through which RNA passes during degradation is visible at the center of the protein complex"] ::
The exosome complex (or PM/Scl complex, often just called the exosome) is a multi-protein intracellular 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 3′ end 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 for cancer function by blocking the activity of the exosome. In addition, mutations in exosome component 3 cause pontocerebellar hypoplasia and spinal motor neuron disease.
Discovery
The exosome was first discovered as an RNase in 1997 in the budding yeast Saccharomyces cerevisiae, an often-used model organism.{{cite journal |last1=Mitchell |title=The Exosome: A Conserved Eukaryotic RNA Processing Complex Containing Multiple 3′→5′ Exoribonucleases |journal=Cell |year=1997 |volume=91 |first1=P |issue=4 |pages=457–466 |pmid=9390555 |doi=10.1016/S0092-8674(00)80432-8 |last2=Petfalski |first2=E |last3=Shevchenko |first3=A |last4=Mann |first4=M |last5=Tollervey |first5=D|s2cid=16035676 |doi-access=free |last1=Allmang |title=The yeast exosome and human PM-Scl are related complexes of 3' → 5' exonucleases |journal=Genes & Development |year=1999 |volume=13 |first1=C |issue=16 |pages=2148–58 |pmid=10465791 |doi=10.1101/gad.13.16.2148 |last2=Petfalski |first2=E |last3=Podtelejnikov |first3=A |last4=Mann |first4=M |last5=Tollervey |first5=D |last6=Mitchell |first6=P |pmc=316947}} Purification of this "PM/Scl complex" allowed the identification of more human exosome proteins and eventually the characterization of all components in the complex.{{cite journal |last1=Brouwer |title=Three novel components of the human exosome |year=2001 |journal=Journal of Biological Chemistry |volume=276 |first1=R |pages=6177–84 |pmid=11110791 |doi=10.1074/jbc.M007603200 |last2=Allmang |first2=C |last3=Raijmakers |first3=R |last4=Van Aarssen |first4=Y |last5=Egberts |first5=WV |last6=Petfalski |first6=E |last7=Van Venrooij |first7=WJ |last8=Tollervey |first8=D |last9=Pruijn |first9=GJ |issue=9 |doi-access=free |hdl=2066/186951 |hdl-access=free |last1=Chen |title=AU binding proteins recruit the exosome to degrade ARE-containing mRNAs |year=2001 |journal=Cell |volume=107 |first1=CY |pages=451–64 |pmid=11719186 |doi=10.1016/S0092-8674(01)00578-5 |last2=Gherzi |first2=R |last3=Ong |first3=SE |last4=Chan |first4=EL |last5=Raijmakers |first5=R |last6=Pruijn |first6=GJ |last7=Stoecklin |first7=G |last8=Moroni |first8=C |last9=Mann |first9=M |last10=Karin |first10=Michael |issue=4|s2cid=14817671 |display-authors=8 |doi-access=free |last1=Koonin |title=Prediction of the archaeal exosome and its connections with the proteasome and the translation and transcription machineries by a comparative-genomic approach |journal=Genome Research |year=2001 |volume=11 |first1=EV |issue=2 |pages=240–52 |pmid=11157787 |doi=10.1101/gr.162001 |last2=Wolf |first2=YI |last3=Aravind |first3=L |pmc=311015|authorlink1=Koonin |last1=Evguenieva-Hackenberg |title=An exosome-like complex in Sulfolobus solfataricus |journal=EMBO Reports |year=2003 |volume=4 |first1=E |issue=9 |pages=889–93 |pmid=12947419 |doi=10.1038/sj.embor.embor929 |last2=Walter |first2=P |last3=Hochleitner |first3=E |last4=Lottspeich |first4=F |last5=Klug |first5=G |pmc=1326366 }}
Structure
Core proteins
::figure[src="https://upload.wikimedia.org/wikipedia/commons/a/a2/Exosome_crystal_structure.png" caption="legend]] below."] ::
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.{{cite book |last1=Schilders |title=Cell and Molecular Biology of the Exosome: How to Make or Break an RNA |year=2006 |volume=251 |first1=G |pages=159–208 |pmid=16939780 |doi=10.1016/S0074-7696(06)51005-8 |last2=Van Dijk |first2=E |last3=Raijmakers |first3=R |last4=Pruijn |first4=GJ|series=International Review of Cytology |isbn=9780123646552 |last1=Lorentzen |title=The archaeal exosome core is a hexameric ring structure with three catalytic subunits |journal=Nature Structural & Molecular Biology |year=2005 |volume=12 |first1=E |pages=575–81 |pmid=15951817 |doi=10.1038/nsmb952 |last2=Walter |first2=P |last3=Fribourg |first3=S |last4=Evguenieva-Hackenberg |first4=E |last5=Klug |first5=G |last6=Conti |first6=E |issue=7|s2cid=2003922 |last1=Shen |title=A view to a kill: structure of the RNA exosome |journal=Cell |year=2006 |volume=127 |first1=V |pages=1093–5 |pmid=17174886 |doi=10.1016/j.cell.2006.11.035 |last2=Kiledjian |first2=M |issue=6 |pmc=1986773}} Of these six eukaryotic proteins, three resemble the archaeal Rrp41 protein and the other three proteins are more similar to the archaeal Rrp42 protein.{{cite journal |last1=Raijmakers |title=Protein-protein interactions between human exosome components support the assembly of RNase PH-type subunits into a six-membered PNPase-like ring |journal=Journal of Molecular Biology |year=2002 |volume=323 |first1=R |pages=653–63 |pmid=12419256 |doi=10.1016/S0022-2836(02)00947-6 |last2=Egberts |first2=WV |last3=Van Venrooij |first3=WJ |last4=Pruijn |first4=GJ |issue=4|hdl=2066/186665 |hdl-access=free ::figure[src="https://upload.wikimedia.org/wikipedia/commons/9/9c/Exosome_schematic.png" caption="legend]] below."] ::
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).{{cite journal |last1=Walter |title=Characterization of native and reconstituted exosome complexes from the hyperthermophilic archaeon Sulfolobus solfataricus |journal=Molecular Microbiology |year=2006 |volume=62 |first1=P |pages=1076–89 |pmid=17078816 |doi=10.1111/j.1365-2958.2006.05393.x |last2=Klein |first2=F |last3=Lorentzen |first3=E |last4=Ilchmann |first4=A |last5=Klug |first5=G |last6=Evguenieva-Hackenberg |first6=E |issue=4 |s2cid=27114625 |doi-access=
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.{{cite journal |last1=Ishii |title=Crystal structure of the tRNA processing enzyme RNase PH from Aquifex aeolicus |journal=Journal of Biological Chemistry |volume=278 |pages=32397–404 |first1=R |year=2003 |pmid=12746447 |doi=10.1074/jbc.M300639200 |last2=Nureki |first2=O |last3=Yokoyama |first3=S |issue=34 |doi-access=free |last1= Harlow |title=Crystal structure of the phosphorolytic exoribonuclease RNase PH from Bacillus subtilis and implications for its quaternary structure and tRNA binding |journal=Protein Science |year=2004 |volume=13 |first1= LS |pages=668–77 |pmid=14767080 |doi=10.1110/ps.03477004 |last2= Kadziola |first2= A |last3= Jensen |first3= KF |last4= Larsen |first4= S |issue= 3 |pmc= 2286726 }} 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.{{cite journal |last1= Symmons |title=A duplicated fold is the structural basis for polynucleotide phosphorylase catalytic activity, processivity, and regulation |journal=Structure |year=2000 |volume=8 |first1= MF |pages=1215–26 |pmid=11080643 |doi=10.1016/S0969-2126(00)00521-9 |last2= Jones |first2= GH |last3= Luisi |first3= BF |issue= 11 |doi-access=free }} Because of this high similarity in both protein domains and structure, these complexes are thought to be evolutionarily related and have a common ancestor.{{cite journal |last1=Lin-Chao |first1=S |last2=Chiou |first2=NT |last3=Schuster |first3=G |title=The PNPase, exosome and RNA helicases as the building components of evolutionarily-conserved RNA degradation machines |journal=Journal of Biomedical Science |year=2007 |volume=14 |pages=523–32 |doi=10.1007/s11373-007-9178-y |pmid=17514363 |issue=4|doi-access=free
Associated proteins
Besides these nine core exosome proteins, two other proteins often associate with the complex in eukaryotic organisms. Rrp44One 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.{{cite journal |title=Endonucleolytic RNA cleavage by a eukaryotic exosome |last1= Lebreton |journal=Nature |year=2008 |volume=456 |first1=A |pages=993–6 |pmid=19060886 |doi=10.1038/nature07480 |last2=Tomecki |first2=R |last3=Dziembowski |first3=A |last4=Séraphin |first4=B |issue=7224|bibcode= 2008Natur.456..993L |s2cid= 1808371 |url= https://hal-ens.archives-ouvertes.fr/hal-01350769/file/Exosome_endo_post-print.pdf |title=The N-terminal PIN domain of the exosome subunit Rrp44 harbors endonuclease activity and tethers Rrp44 to the yeast core exosome. |last1= Schneider |journal=Nucleic Acids Research |year=2009 |volume=37 |first1=C |pages=1127–40 |pmid=19129231 |doi=10.1093/nar/gkn1020 |last2=Leung |first2=E |last3=Brown |first3=J |last4=Tollervey |first4=D |issue=4 |pmc=2651783}} In yeast, Rrp44 is associated with all exosome complexes and has a crucial role in the activity of the yeast exosome complex.{{cite journal |title=The exosome subunit Rrp44 plays a direct role in RNA substrate recognition |last1= Schneider |journal=Molecular Cell |year=2007 |volume=27 |first1=C |pages=324–31 |pmid=17643380 | pmc=7610968| doi=10.1016/j.molcel.2007.06.006 |last2=Anderson |first2=JT |last3=Tollervey |first3=D |issue=2|url= https://epublications.marquette.edu/cgi/viewcontent.cgi?article=1439&context=bio_fac |last1=Staals |first1=RH |last2=Bronkhorst |first2=AW |last3=Schilders |first3=G |last4=Slomovic |first4=S |last5=Schuster |first5=G |last6=Heck |first6=AJ |last7=Raijmakers |first7=R |last8=Pruijn |first8=GJ |title=Dis3-like 1: a novel exoribonuclease associated with the human exosome. |journal=The EMBO Journal |volume=29 |issue=14 |pages=2358–67 |year=2010 |pmid=20531389 |pmc=2910272 |doi=10.1038/emboj.2010.122 |last1=Tomecki |first1=R |last2=Kristiansen |first2=MS |last3=Lykke-Andersen |first3=S |last4=Chlebowski |first4=A |last5=Larsen |first5=KM |last6=Szczesny |first6=RJ |last7=Drazkowska |first7=K |last8=Pastula |first8=A |last9=Andersen |first9=JS |last10=Stepien |first10=Piotr P |last11=Dziembowski |first11=Andrzej |last12=Jensen |first12=Torben Heick |title=The human core exosome interacts with differentially localized processive RNases: hDIS3 and hDIS3L |journal=The EMBO Journal |volume=29 |issue=14 |pages=2342–57 |year=2010 |pmid=20531386 |pmc=2910271 |doi=10.1038/emboj.2010.121 |display-authors=8 ::figure[src="https://upload.wikimedia.org/wikipedia/commons/f/f1/Partial_Rrp6_structure.png" caption="2hbj}} with [[α-helices]] in red and [[β-sheets]] in yellow.]] 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]] protein family.{{cite journal"] ::
|last1=Mian |first1=IS |title=Comparative sequence analysis of ribonucleases HII, III, II PH and D |journal=Nucleic Acids Research |year=1997 |volume=25 |pages=3187–3195 |pmid=9241229 |doi=10.1093/nar/25.16.3187 |issue=16 |pmc=146874}} 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.{{cite journal |last1=Raijmakers |title=The exosome, a molecular machine for controlled RNA degradation in both nucleus and cytoplasm |journal=European Journal of Cell Biology |year=2004 |volume=83 |first1=R |pages=175–83 |pmid=15346807 |doi=10.1078/0171-9335-00385 |last2=Schilders |first2=G |last3=Pruijn |first3=GJ |issue=5|url=https://repository.ubn.ru.nl//bitstream/handle/2066/57577/57577.pdf
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, which includes an RNA helicase (Ski2) and is involved in mRNA degradation.{{cite journal |last1=Wang |title=Domain interactions within the Ski2/3/8 complex and between the Ski complex and Ski7p |journal=RNA |year=2005 |volume=11 |first1=L |pages=1291–302 |pmid=16043509 |doi=10.1261/rna.2060405 |last2=Lewis |first2=MS |last3=Johnson |first3=AW |issue=8 |pmc=1370812 }} 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.{{cite journal |last1=LaCava |title=RNA degradation by the exosome is promoted by a nuclear polyadenylation complex |journal=Cell |year=2005 |first1=J |volume=121 |pages=713–24 |pmid=15935758 |doi=10.1016/j.cell.2005.04.029 |last2=Houseley |first2=J |last3=Saveanu |first3=C |last4=Petfalski |first4=E |last5=Thompson |first5=E |last6=Jacquier |first6=A |last7=Tollervey |first7=D |issue=5 |s2cid=14898055 |doi-access=free
Function
Enzymatic function
::figure[src="https://upload.wikimedia.org/wikipedia/commons/7/71/3'_RNA_degradation.png" caption="Reaction diagrams for both hydrolytic (left) and phosphorolytic (right) 3' end degradation of RNA."] ::
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, 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 diphosphates. The hydrolytic enzymes use water to hydrolyse 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.{{cite journal |last1=Liu |title=Erratum: Reconstitution, activities, and structure of the eukaryotic RNA exosome |journal= Cell |year=2007 |volume=131 |first1=Q |pages=188–189 |doi=10.1016/j.cell.2007.09.019 |last2=Greimann |first2=JC |last3=Lima |first3=CD |issue=1 |doi-access=free |last1=Dziembowski |title=A single subunit, Dis3, is in essence responsible for yeast exosome core activity |journal=Nature Structural & Molecular Biology |year=2007 |volume=14 |first1=A |pages=15–22 |pmid=17173052 |doi=10.1038/nsmb1184 |last2=Lorentzen |first2=E |last3=Conti |first3=E |last4=Séraphin |first4=B |issue=1 |s2cid=24691764 |last1=Liu |title=Reconstitution, activities, and structure of the eukaryotic RNA exosome |journal= Cell |year=2006 |volume=127 |first1=Q |pages=1223–37 |pmid=17174896 |doi=10.1016/j.cell.2006.10.037 |last2=Greimann |first2=JC |last3=Lima |first3=CD |issue=6 |s2cid=62785677 |doi-access=free |last1=Lorentzen |title=Structural basis of 3' end RNA recognition and exoribonucleolytic cleavage by an exosome RNase PH core |journal=Molecular Cell |year=2005 |first1=E |volume=20 |pages=473–81 |pmid=16285928 |doi=10.1016/j.molcel.2005.10.020 |last2=Conti |first2=E |issue=3|doi-access=free
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.
::figure[src="https://upload.wikimedia.org/wikipedia/commons/2/2d/Exosome_active_subunits_simple.png" caption="below]] for a full legend."] ::
Substrates
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. 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.{{cite journal |last1= LeJeune |title=Nonsense-mediated mRNA decay in mammalian cells involves decapping, deadenylating, and exonucleolytic activities |journal=Molecular Cell |year=2003 |volume=12 |first1= F |pages=675–87 |pmid=14527413 |doi=10.1016/S1097-2765(03)00349-6 |last2= Li |first2= X |last3= Maquat |first3= LE |issue= 3 |doi-access=free |last1= Wilson |title=A genomic screen in yeast reveals novel aspects of nonstop mRNA metabolism |journal=Genetics |year=2007 |pmid=17660569 |first1= MA |doi=10.1534/genetics.107.073205 |volume=177 |pages=773–84 |last2= Meaux |first2= S |last3= Van Hoof |first3= A |issue= 2 |pmc= 2034642 }}{{cite journal |last1= Lin |title=Localization of AU-rich element-containing mRNA in cytoplasmic granules containing exosome subunits |journal=Journal of Biological Chemistry |year=2007 |volume=282 |first1= WJ |pages=19958–68 |pmid=17470429 |doi=10.1074/jbc.M702281200 |last2= Duffy |first2= A |last3= Chen |first3= CY |issue= 27 |doi-access=free |last1= Allmang |title=Functions of the exosome in rRNA, snoRNA and snRNA synthesis |journal=EMBO Journal |year=1999 |first1= C |volume=18 |pages=5399–410 |pmid=10508172 |doi=10.1093/emboj/18.19.5399 |last2= Kufel |first2= J |last3= Chanfreau |first3= G |last4= Mitchell |first4= P |last5= Petfalski |first5= E |last6= Tollervey |first6= D |issue= 19 |pmc= 1171609 }} 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.{{cite journal |last1= Schilders |title=MPP6 is an exosome-associated RNA-binding protein involved in 5.8S rRNA maturation |journal=Nucleic Acids Research |year=2005 |volume=33 |first1= G |pages=6795–804 |pmid=16396833 |doi=10.1093/nar/gki982 |last2= Raijmakers |first2= R |last3= Raats |first3= JM |last4= Pruijn |first4= GJ |issue= 21 |pmc= 1310903 }}
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 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.{{cite journal |last1=van Dijk |first1=EL |last2=Schilders |first2=G |last3=Pruijn |first3=GJ |title=Human cell growth requires a functional cytoplasmic exosome, which is involved in various mRNA decay pathways |journal=RNA |year=2007 |volume=13 |pages=1027–35 |pmid=17545563 |doi=10.1261/rna.575107 |issue=7 |pmc=1894934}} Bacteria do not have an exosome complex; however, similar functions are performed by a simpler complex that includes the protein PNPase, called the degradosome.{{cite journal |last1=Carpousis AJ |first1=AJ |title=The Escherichia coli RNA degradosome: structure, function and relationship in other ribonucleolytic multienzyme complexes |journal=Biochem. Soc. Trans. |volume=30 |issue=2 |pages=150–5 |year=2002 |pmid=12035760 |doi=10.1042/BST0300150}} ::figure[src="https://upload.wikimedia.org/wikipedia/commons/7/72/Exosome_core_with_RNA.png" caption="Two core subunits of the archaeal exosome (Rrp41 and Rrp42), bound to a small RNA molecule (in red)."] ::
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. It is presumed that this system prevents aberrant complexes from interfering with important cellular processes such as protein synthesis.{{cite journal |vauthors = Houseley J, LaCava J, Tollervey D |title=RNA-quality control by the exosome |journal=Nat. Rev. Mol. Cell Biol. |volume=7 |issue=7 |pages=529–39 |date=July 2006 |pmid=16829983 |doi=10.1038/nrm1964 |s2cid=22499032
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.{{cite journal |last1=Wyers F |first1=F |last2=Rougemaille |first2=M |last3=Badis |first3=G |last4=Rousselle |first4=JC |last5=Dufour |first5=ME |last6=Boulay |first6=J |last7=Régnault |first7=B |last8=Devaux |first8=F |last9=Namane |first9=A |title=Cryptic pol II transcripts are degraded by a nuclear quality control pathway involving a new poly(A) polymerase |journal=Cell |volume=121 |issue=5 |pages=725–37 |date=June 2005 |pmid=15935759 |doi=10.1016/j.cell.2005.04.030 |s2cid=1390706 |display-authors=3 |doi-access=free |vauthors = Neil H, Malabat C, d'Aubenton-Carafa Y, Xu Z, Steinmetz LM, Jacquier A |title=Widespread bidirectional promoters are the major source of cryptic transcripts in yeast |journal=Nature |volume=457 |issue=7232 |pages=1038–42 |date=February 2009 |pmid=19169244 |doi=10.1038/nature07747 |bibcode=2009Natur.457.1038N |s2cid=4329373 |last1=Preker P |first1=P |last2=Nielsen |first2=J |last3=Kammler |first3=S |last4=Lykke-Andersen |first4=S |last5=Christensen |first5=MS |last6=Mapendano |first6=CK |last7=Schierup |first7=MH |last8=Jensen |first8=TH |title=RNA exosome depletion reveals transcription upstream of active human promoters |journal=Science |volume=322 |issue=5909 |pages=1851–4 |date=December 2008 |pmid=19056938 |doi=10.1126/science.1164096 |display-authors=3 |bibcode=2008Sci...322.1851P |doi-access=free
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 and either polymyositis or dermatomyositis.{{cite journal |last1= J.E. Pope |first1= JE |title=Scleroderma overlap syndromes |journal=Current Opinion in Rheumatology |year=2002 |volume=14 |pages=704–10 |pmid=12410095 |doi=10.1097/00002281-200211000-00013 |issue= 6 }} 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.{{cite journal |doi=10.1111/j.1365-2249.1990.tb05291.x |last1=Gelpi |title=Identification of protein components reactive with anti-PM/Scl autoantibodies |journal=Clinical and Experimental Immunology |volume=81 |first1=C |year=1991 |pages=59–64 |pmid=2199097 |last2=Algueró |first2=A |last3=Angeles Martinez |first3=M |last4=Vidal |first4=S |last5=Juarez |first5=C |last6=Rodriguez-Sanchez |first6=JL |issue=1 |pmc=1535032}} 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.{{cite journal |last1=Targoff |title=Nucleolar localization of the PM-Scl antigen |journal=Arthritis & Rheumatism |volume=28 |first1=IN |year=1985 |pages=226–30 |pmid=3918546 |doi=10.1002/art.1780280221 |last2=Reichlin |first2=M |issue=2 |doi-access=
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.{{cite journal |last1=Raijmakers |title=PM-Scl-75 is the main autoantigen in patients with the polymyositis/scleroderma overlap syndrome |journal=Arthritis & Rheumatism |year=2004 |first1=R |volume=50 |pages=565–9 |pmid=14872500 |doi=10.1002/art.20056 |last2=Renz |first2=M |last3=Wiemann |first3=C |last4=Egberts |first4=WV |last5=Seelig |first5=HP |last6=Van Venrooij |first6=WJ |last7=Pruijn |first7=GJ |issue=2 |doi-access= |last1= Brouwer |title=Autoantibodies directed to novel components of the PM/Scl complex, the human exosome |journal=Arthritis Research & Therapy |year=2002 |volume=4 |first1= R |pages=134–8 |pmid=11879549 |doi=10.1186/ar389 |last2= Vree Egberts |first2= WT |last3= Hengstman |first3= GJ |last4= Raijmakers |first4= R |last5= Van Engelen |first5= BG |last6= Seelig |first6= HP |last7= Renz |first7= M |last8= Mierau |first8= R |last9= Genth |first9= E |last10=Pruijn |first10=Ger JM |last11=Van Venrooij |first11=Walther J |issue= 2 |pmc= 83843 |display-authors=8 |doi-access=free |last1= Schilders |title=C1D is a major autoantibody target in patients with the polymyositis-scleroderma overlap syndrome |journal=Arthritis & Rheumatism |year=2007 |volume=56 |first1= G |pages=2449–54 |pmid=17599775 |doi=10.1002/art.22710 |last2= Egberts |first2= WV |last3= Raijmakers |first3= R |last4= Pruijn |first4= GJ |issue= 7 |hdl= 2066/35047 |hdl-access= free |last1=Mahler |title=Clinical evaluation of autoantibodies to a novel PM/Scl peptide antigen |journal=Arthritis Research & Therapy |year=2005 |volume=7 |first1=M |pages=R704–13 |pmid=15899056 |doi=10.1186/ar1729 |last2=Raijmakers |first2=R |last3=Dähnrich |first3=C |last4=Blüthner |first4=M |last5=Fritzler |first5=MJ |issue=3 |pmc=1174964 |doi-access=free
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, arthritis, myositis and scleroderma.{{cite journal |last1=Mahler |title=Novel aspects of autoantibodies to the PM/Scl complex: Clinical, genetic and diagnostic insights |journal=Autoimmunity Reviews |year=2007 |first1=M |volume=6 |pages=432–7 |pmid=17643929 |doi=10.1016/j.autrev.2007.01.013 |last2=Raijmakers |first2=R |issue=7 }} Treatment of these patients is symptomatic and is similar to treatment for the individual autoimmune disease, often involving either immunosuppressive or immunomodulating drugs.{{cite journal |last1= Jablonska |title=Scleromyositis: a scleroderma/polymyositis overlap syndrome |journal=Clinical Rheumatology |year=1998 |first1= S |volume=17 |pages=465–7 |pmid=9890673 |doi=10.1007/BF01451281 |last2= Blaszczyk |first2= M |issue= 6 |s2cid=39237322
Cancer treatment
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.{{cite journal |last1=Lum |title=Discovering modes of action for therapeutic compounds using a genome-wide screen of yeast heterozygotes |journal=Cell |year=2004 |volume=116 |first1=PY |pages=121–37 |pmid=14718172 |doi=10.1016/S0092-8674(03)01035-3 |last2=Armour |first2=CD |last3=Stepaniants |first3=SB |last4=Cavet |first4=G |last5=Wolf |first5=MK |last6=Butler |first6=JS |last7=Hinshaw |first7=JC |last8=Garnier |first8=P |last9=Prestwich |first9=GD |last10=Leonardson |first10=Amy |last11=Garrett-Engele |first11=P |last12=Rush |first12=C. M. |last13=Bard |first13=M |last14=Schimmack |first14=G |last15=Phillips |first15=J. W. |last16=Roberts |first16=C. J. |last17=Shoemaker |first17=D. D. |issue=1 |s2cid=11922219 |display-authors=8 |doi-access=free
Neurological disorders
Mutations in exosome component 3 cause infantile spinal motor neuron disease, cerebellar atrophy, progressive microcephaly and profound global developmental delay, consistent with pontocerebellar hypoplasia type 1B (PCH1B; MIM 614678).{{Cite journal | last1 = Wan | first1 = J. | last2 = Yourshaw | first2 = M. | last3 = Mamsa | first3 = H. | last4 = Rudnik-Schöneborn | first4 = S. | last5 = Menezes | first5 = M. P. | last6 = Hong | first6 = J. E. | last7 = Leong | first7 = D. W. | last8 = Senderek | first8 = J. | last9 = Salman | first9 = M. S. | last10 = Chitayat | doi = 10.1038/ng.2254 | first10 = D. | last11 = Seeman | first11 = P. | last12 = Von Moers | first12 = A. | last13 = Graul-Neumann | first13 = L. | last14 = Kornberg | first14 = A. J. | last15 = Castro-Gago | first15 = M. | last16 = Sobrido | first16 = M. A. J. S. | last17 = Sanefuji | first17 = M. | last18 = Shieh | first18 = P. B. | last19 = Salamon | first19 = N. | last20 = Kim | first20 = R. C. | last21 = Vinters | first21 = H. V. | last22 = Chen | first22 = Z. | last23 = Zerres | first23 = K. | last24 = Ryan | first24 = M. M. | last25 = Nelson | first25 = S. F. | last26 = Jen | first26 = J. C. | title = Mutations in the RNA exosome component gene EXOSC3 cause pontocerebellar hypoplasia and spinal motor neuron degeneration | journal = Nature Genetics | volume = 44 | issue = 6 | pages = 704–708 | year = 2012 | pmid = 22544365 | pmc =3366034
List of subunits
::data[format=table]
| Legend | General name | Domains | Human | Yeast (S. cerevisiae) | Archaea | MW (kD) | Human gene | Yeast gene |
|---|---|---|---|---|---|---|---|---|
| 1 | Csl4 | S1 RBD | hCsl4 | Csl4p/Ski4p | Csl4 | 21–32 | EXOSC1 | |
| 2 | Rrp4 | S1/KH RBD | hRrp4 | Rrp4p | Rrp4 | 28–39 | EXOSC2 | |
| 3 | Rrp40 | S1/KH RBD | hRrp40 | Rrp40p | (Rrp4) | 27–32 | EXOSC3 | |
| 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 | |
| 8 | Rrp43 | RNase PH | OIP2 | Rrp43p | (Rrp42) | 30–44 | EXOSC8 | |
| 9 | Rrp45 | RNase PH | PM/Scl-75 | Rrp45p | (Rrp42) | 34–49 | EXOSC9 | |
| 10 | Rrp6 | RNase D | PM/Scl-100 | Rrp6p | n/a | 84–100 | EXOSC10 | |
| 11 | Rrp44 | RNase R | Dis3 | Rrp44p/Dis3p | n/a | 105–113 | DIS3 | |
| :: |
- 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.
References
References
- (1997-11-14). "The exosome: a conserved eukaryotic RNA processing complex containing multiple 3'-->5' exoribonucleases". Cell.
- (2007-08-01). "Novel aspects of autoantibodies to the PM/Scl complex: Clinical, genetic and diagnostic insights". Autoimmunity Reviews.
- (2014-02-27). "Clinical and Serologic Correlates of Anti-PM/Scl Antibodies in Systemic Sclerosis: A Multicenter Study of 763 Patients". Arthritis & Rheumatology.
- (2008-06-01). "The RNA Exosome Component hRrp6 Is a Target for 5-Fluorouracil in Human Cells". Molecular Cancer Research.
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