Regulation of transcriptome plasticity by mTOR signaling pathway

Abstract

The mechanistic target of rapamycin (mTOR) pathway, long recognized for its critical roles in cellular metabolism and growth, is increasingly appreciated for its regulatory impact on the transcriptome. Recent insights into mTOR's regulation of alternative splicing and polyadenylation reveal a sophisticated mechanism by which mTOR influences RNA processing to affect the proteome's diversity and functionality. Here, in this Review, we delve into the multifaceted roles of mTOR in modulating transcriptome plasticity, highlighting its influence beyond traditional functions such as protein synthesis and cell growth. By examining the latest findings, we explore how mTOR-mediated transcriptome plasticity plays a pivotal role in cellular adaptation and pathogenesis. Studies indicate that mTOR modulation of RNA processing pathways enables cells to respond dynamically to environmental and metabolic cues, thereby altering protein function and cellular behavior in a context-dependent manner. This capability is crucial for both normal physiological responses and the development of disease. The Review also discusses the implications of these findings for understanding complex biological systems and diseases, particularly cancer, where mTOR's regulation of transcript diversity could drive tumor heterogeneity and treatment resistance. As research continues to uncover the extensive influence of mTOR on RNA processing, it becomes clear that a comprehensive understanding of these mechanisms is essential for the development of targeted therapies and the prediction of their outcomes in clinical settings.

Fig. 1. mTOR complexes, along with their key upstream regulators and downstream target pathways.

The diagram illustrates representative components of mTORC1 and mTORC2.

Fig. 2. Schematic of splicing and alternative splicing.

a An illustration of cis- and trans-acting factors involved in pre-mRNA splicing, highlighting four essential cis-acting elements recognized by U snRNPs and splicing factors, including U2AF heterodimers. b Classification of alternative splicing types, with exon skipping also referred to as cassette-type splicing.

Fig. 3. Schematic of APA.

a There are two main types of APA. The first type, known as 3′-UTR APA, occurs within the 3′-UTR of a gene and does not alter the gene’s coding capacity but may result in shortened transcripts that evade regulation by miRNAs and RBPs. The second type occurs within introns, leading to truncated mRNAs and potentially truncated proteins. b Cis- and trans-acting factors in polyadenylation: multiple polyadenylation factors recognize distinct sequence elements around the polyadenylation signal (PAS) in 3′-UTRs. c Intronic polyadenylation utilizes PASs found in introns. The choice between splicing and intronic polyadenylation is influenced by the cellular and disease context, with both processes competing for the same pre-mRNA.

Fig. 4. mTOR-regulated APA and its impact on the proteome.

mTOR influences the profiles of both 3′-UTR APA and intronic APA. 3′-UTR APA typically enhances translation, whereas intronic APA can lead to both increases and decreases in transcript levels. In cases of intronic APA, the effects on the proteome are predominantly associated with the gain or loss of functional protein domains, significantly altering protein functionality.

Fig. 5. mTOR-coordinated alternative splicing and its impact on the proteome.

a mTOR influences a variety of splicing factors and RBPs, leading to changes in the alternative splicing patterns of genes involved in lipid biogenesis, cellular homeostasis and lifespan. mTOR also alters the stoichiometry of the essential splicing factor U2AF1, impacting 5′-UTR alternative splicing and modifying protein synthesis efficiency. b Generally, mTOR activation promotes exon skipping, which results in varied outcomes for the proteome, dependent on the locations of the alternative splicing events within the mRNAs. 5′-UTR alternative splicing often leads to truncation at the N-terminus of proteins or alters mRNA translational efficiency. In coding regions, alternative splicing can result in the gain or loss of protein functional domains, and sometimes transforms coding mRNA into noncoding transcripts.