Exosome complex
[12][13] 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.
[14] 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 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.
[23] 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.
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.
[25] 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.
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.
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.
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.
[36] 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.
[37][38] The importance of these unstable RNAs and their degradation are still unclear, but similar RNA species have also been detected in human cells.
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.
[41] 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.
[42] 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 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.
[49] 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).
