Overview of mRNA Degradation Pathways
Process of mRNA Degradation
The first step in mRNA degradation is the removal of the 3′ poly(A) tail. This process is mediated by deadenylases, such as the CCR4-NOT and PAN2-PAN3 complexes. PAN2-PAN3 removes longer poly(A) tails, while CCR4-NOT trims shorter tails. After deadenylation, the 5′ cap is removed by the decapping complex DCP1/2. The mRNA is then degraded by exonucleases: the 5′-3′ exonuclease Xrn1 and the 3′-5′ exonuclease exosome complex. These enzymes degrade the mRNA from the exposed ends.
Besides exonucleolytic decay, mRNA can also undergo internal cleavage, known as endonucleolytic decay. This process is part of the mRNA surveillance mechanism called nonsense-mediated decay (NMD), which targets mRNAs with premature stop codons (PTCs). NMD leads to the decapping of the mRNA and degradation by Xrn1. Under certain stress conditions, such as viral infection or hypoxia, NMD is suppressed.
RNA Granules: P-bodies and Stress Granules
mRNA degradation typically occurs in specialized cytoplasmic structures known as RNA granules. P-bodies contain enzymes such as DCP1/2, Xrn1, and CCR4-NOT, which regulate mRNA decay. Stress granules (SGs), which form in response to cellular stress, contain untranslated mRNA and translation initiation factors. These granules play an important role in regulating mRNA stability and translation. Both P-bodies and SGs are dynamic structures that exchange components and help control mRNA turnover.
Virus Interaction with mRNA Degradation Pathways
Viruses often manipulate host cell machinery to avoid mRNA degradation and promote their own replication. For example, flaviviruses, including West Nile virus (WNV) and dengue virus (DV), inhibit stress granule formation by interfering with SG components. Hepatitis C virus (HCV) reduces P-body numbers and repositions P-body components to viral replication sites. These viral strategies help ensure efficient replication and evade cellular defense mechanisms that normally target viral mRNA for degradation.