The organization and regulation of mRNA-protein complexes

Abstract

In a eukaryotic cell, each messenger RNA (mRNA) is bound to a variety of proteins to form an mRNA-protein complex (mRNP). Together, these proteins impact nearly every step in the life cycle of an mRNA and are critical for the proper control of gene expression. In the cytoplasm, for instance, mRNPs affect mRNA translatability and stability and provide regulation of specific transcripts as well as global, transcriptome-wide control. mRNPs are complex, diverse, and dynamic, and so they have been a challenge to understand. But the advent of high-throughput sequencing technology has heralded a new era in the study of mRNPs. Here, I will discuss general principles of cytoplasmic mRNP organization and regulation. Using microRNA-mediated repression as a case study, I will focus on common themes in mRNPs and highlight the interplay between mRNP composition and posttranscriptional regulation. mRNPs are an important control point in regulating gene expression, and while the study of these fascinating complexes presents remaining challenges, recent advances provide a critical lens for deciphering gene regulation. WIREs RNA 2017, 8:e1369. doi: 10.1002/wrna.1369 For further resources related to this article, please visit the WIREs website.

Figure 1

RNA elements and proteins combine to form an mRNP. Translation initiation factors, such as eIF4E and eIF4G, interact with the 5′UTR and cap, while PABP binds the 3′ poly(A) tail. Because the cap and poly(A) are found on nearly all transcripts, these proteins are considered core factors. In contrast, regulatory factors recognize specific motifs, often in the 3′UTR, and so bind and regulate a specific subset of transcripts.

Figure 2

The closed loop model. By binding simultaneously to eIF4E and PABP, which in turn bind the 5′ cap and 3′ poly(A) tail, eIF4G forms a protein bridge that brings the two transcript ends together and allows regulatory information (such as deadenylation) to be transmitted from the 3′ to 5′ end of an mRNA.

Figure 3

Cytoplasmic mRNA decay. During mRNA decay, the action of the two major cytoplasmic deadenylase complexes (the Pan2–Pan3 complex and the CCR4–NOT complex) leads to shortening of the poly(A) tail and PABP dissociation, although it is currently unclear whether shortening of poly(A) tail leads to the loss of PABP or vice versa. In some cases, deadenylation (or the deadenylase complexes with associated factors) stimulates the dissociation of eIF4E and recruitment of the decapping enzymes. In other cases, deadenylation is followed by uridylation, which serves as a landing pad to stimulate the recruitment of the decapping enzymes. (Note, however, that Saccharomyces cerevisiae lacks TUTases.) Once the message is decapped, the cytoplasmic 5′→3′ exonuclease, Xrn1, degrades the transcript body. In the cytoplasm, 5′→3′ decay represents the major decay pathway, but there are 3′→5′ exonuclease (such as the exosome and Dis3L2) that can degrade deadenylated transcripts and may also act at the same time as 5′→3′ decay.

Figure 4

mRNP reorganization during miRNA‐mediated decay. Argonaute (Ago) is directed to specific transcripts via base‐pairing between the target RNA and the loaded miRNA. TNRC6, which interacts with Ago, then stimulates mRNA decay via the recruitment of additional factors. TNRC6 interacts with PABP, which may stimulate its dissociation. It also interacts with the CCR4–NOT deadenylase complex and the Pan2–Pan3 deadenylase complex, which triggers deadenylation. In addition, CNOT1, a large scaffold protein in the CCR4–NOT complex, interacts with the decapping activator, DDX6, which in turn interacts with 4E‐T. In addition to interacting with the decapping enzyme, 4E‐T also interacts with eIF4E itself and may stimulate its dissociation from the target.