Exosome 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. 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 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. 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 that they use inorganic phosphate to remove nucleotides from the 3' end of RNA molecules. 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. 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).