RNA Exosomes

By Jennifer McDowall

Post-transcriptional mRNA processing in eukaryotes is a multi-step process involving processing enzymes and quality control procedures. Processing of pre-mRNAs begins in the nucleus with the removal of introns by the spliceosome. The spliceosome is a protein-RNA complex consisting of different small nuclear ribonucleoproteins or snRNPs (U1, U2, U4/U6, U5), each of which is composed of a uridine-rich snRNA and a ring of Sm proteins.

Quality control of processed and unprocessed mRNA helps rid the cell of incorrectly processed and nonsense transcripts. This clears the cell of ‘junk’ mRNA, as well as freeing up nucleotides to be re-used in the transcriptional process. Even correctly processed mRNAs will eventually be degraded as part of the cell’s turnover of mRNA. This is not a random process; mRNA turnover is tightly controlled by the presence of specific sequences within the mRNA molecule and by various factors that can act upon it.

The turnover of mRNA is a major controlling factor in the expression of a gene, the relative abundance of a transcript being a balancing act between transcription and degradation. The stability of a given mRNA transcript governs its relative cellular abundance, its time-span in circulation and its distribution within a cell. For example, transcripts with a long half-life include those with housekeeping functions (e.g. metabolic enzymes), while those with shorter half-lives include cell-cycle regulators, transcription factors, growth factors, and circadian regulators, many of which are inducible. Elements within an mRNA transcript help determine its stability, such as the presence of AU-rich elements (AREs), which tag inducible mRNAs (including oncogenes and cytokines) for short half-lives. AREs act as regulators of mRNA stability by stimulating decapping and deadenylation, processes that have key roles in mRNA turnover. They do this through the recruitment of AU-binding proteins (AUBPs) that bind the ARE-containing transcripts. How AUBPs alter mRNA decay is not known, but it could involve recruitment of exosomes on mRNAs to be degraded.

Exosomes, Processing, Degrading, and Quality Control of RNA

Exosomes are the cell’s machinery for RNA processing and degradation, functioning as nano-compartments within the nucleus or cytoplasm in a similar manner to the degradation of proteins by proteasomes. Exosomes act on several types of RNA, including mRNA transcripts, as well as non-coding RNAs such as ribosomal rRNA, snRNA (part of spliceosomes) and snoRNA (small nucleolar RNAs used to process and modify snRNA and rRNA). Exosomes carry out processive degradation, either completely degrading the RNA, or carrying out a more limited degradation as required for processing of certain RNAs. Exosome functions includes:

· Normal turnover of cytoplasmic mRNA.

· Quality control of pre-mRNA (both incorrectly processed mRNAs and nonsense-mediated decay); participates in mRNA surveillance pathways.

· Degradation of cryptic nuclear Pol-II transcripts and RNA fragments.

· Processing of non-coding RNAs (rRNA, snRNA and snoRNA).

Next: The Ancient Structure of Exosomes