Abstract
Export of messenger ribonucleic acids (mRNAs) into the cytoplasm is a fundamental step in gene regulation processes, which is meticulously quality controlled by highly efficient mechanisms in eukaryotic cells. Yet, it remains unclear how the aberrant mRNAs are recognized and retained inside the nucleus. Using a new modelling approach for complex systems, namely the agent-based modelling (ABM) approach, we develop a minimal model of the mRNA quality control (QC) mechanism. Our results demonstrate that regulation of the affinity of RNA-binding proteins (RBPs) to export receptors along with the weak interaction between the nuclear basket protein (Mlp1 or Tpr) and RBPs are the minimum requirements to distinguish and retain aberrant mRNAs. Our results show that the affinity between Tpr and RBPs is optimized to maximize the retention of aberrant mRNAs. In addition, we demonstrate how the length of mRNA affects the QC process. Since longer mRNAs spend more time in the nuclear basket to form a compact conformation and initiate their export, nuclear basket proteins could more easily capture and retain them inside the nucleus.
Highlights
The major proteins involved in quality control (QC) of messenger ribonucleic acids (mRNAs) at the nuclear basket of the nuclear pore complex (NPC) can be categorized into two groups, 1) nuclear basket-associated proteins and 2) RNA-binding proteins (RBPs) that are directly bound to mRNAs
We seek to test our hypothesis that the interactions between three types of proteins involved in mRNA export and QC, i.e. the export receptor, RBPs, and Tpr, are the key to distinguish aberrant mRNAs
In order to evaluate whether regulation of the interaction between RBPs and the export receptor is sufficient to retain aberrant mRNAs, we conducted a set of simulations on export of mRNAs with different affinities of RBPs to NXF1/NXT1
Summary
The major proteins involved in QC of mRNAs at the nuclear basket of the NPC can be categorized into two groups, 1) nuclear basket-associated proteins and 2) RBPs that are directly bound to mRNAs. The current proposed model for mRNA export and QC at the nuclear basket[3,19,30] suggests RBPs as adapters for recruitment of export receptor heterodimers (presumably in concert with other elements as cofactors), while, upon initiation of mRNA export through the NPC, Tpr (Mlp1) interacts with RBPs, acting as a checkpoint to verify the maturity of mRNP for export[19,23,24] (Fig. 1) It is still elusive how the collective behaviour of these factors and the kinetics of their interactions could efficiently distinguish aberrant and normal mRNAs. The lack of detailed understanding of mRNA QC mechanism could be partly attributed to the complex nature of this process, which makes it not tractable via experimental and conventional computational approaches. Along with recent single-molecule imaging techniques[37,38], could unveil valuable details of mRNA metabolism with a high spatiotemporal resolution
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
