The Central FacilitaTOR: Coordinating Transcription and Translation in Eukaryotes

Abstract

One of the biggest challenges to eukaryotic gene expression is coordinating transcription in the nucleus and protein synthesis in the cytoplasm. However, little is known about how these major steps in gene expression are connected. The Target of Rapamycin (TOR) signaling pathway is crucial in connecting these critical phases of gene expression. Highly conserved among eukaryotic cells, TOR regulates growth, metabolism, and cellular equilibrium in response to changes in nutrients, energy levels, and stress conditions. This review examines the extensive role of TOR in gene expression regulation. We highlight how TOR is involved in phosphorylation, remodeling chromatin structure, and managing the factors that facilitate transcription and translation. Furthermore, the critical functions of TOR extend to processing RNA, assembling RNA-protein complexes, and managing their export from the nucleus, demonstrating its wide-reaching impact throughout the cell. Our discussion emphasizes the integral roles of TOR in bridging the processes of transcription and translation and explores how it orchestrates these complex cellular processes.

Keywords: RNA export; RNA processing; TOR; mRNA turnover; ribosome biogenesis; stress response; transcription; translation.

Figure 1

Overview of mTOR signaling pathway: The mTOR signaling network consists of two branches, each mediated by a specific complex, mTORC1 and mTORC2. The GATOR1 complex inhibits rapamycin-sensitive mTOR by acting as a GTPase-activating protein for Rag GTPase and, therefore, inhibits mTORC1 by converting the active GTP-bound Rag proteins to inactive GDP-bound forms. GATOR2 is a positive regulator of mTORC1 by inhibiting GATOR1 [15]. Once mTORC1 is activated, it leads to the phosphorylation of LARP1, S6Ks, and 4E-BP, promoting translation [86,87]. Activated mTORC1 also leads to the activation of transcription factors and nuclear/cytoplasmic shuttling of the complex, leading to the upregulation of genes involved in nucleotide biosynthesis, lipid biosynthesis, ribosomal biosynthesis, hypoxia, and others [27,86]. Conversely, activated mTORC2 regulates cell survival, metabolism, and cytoskeletal dynamics by directly phosphorylating AKT (protein kinase B) and others [27,88]. The energy-sensing PI3K-PTEN-AKT-TSC pathway also activates AKT and is a positive regulator of mTORC1 by inhibiting the TSC1/2 (Tuberous Sclerosis) complex [88]. The TSC complex inhibits mTORC1 by serving as a GTPase-activating protein for the Ras homolog Rheb, a small GTPase. Rheb contributes to the activation of mTORC1 by promoting lysosomal surface translocation [16]. Solid lines indicate a direct interaction, and dotted lines indicate an indirect interaction, either from an unknown mechanism or other effectors.

Figure 2

TORC1 can coordinate transcription and translation by regulating ribosome biogenesis in S. cerevisiae. TORC1 plays a pivotal role in ribosomal protein (RP) and ribosomal biogenesis (RiBi) gene expression by regulating RNA Pol I, II, and III through direct and indirect mechanisms and various cofactors [71]. In RNA Pol I-mediated transcription, under optimal, nutrient-rich conditions, TORC1 localizes to the nucleus and associates with chromatin, promoting histone modifications such as H3 acetylation via Rtt109 and Asf1 and H4 deacetylation via Rpd3 [104,181]. TORC1 also facilitates Rrn3-RNA Pol I association and further regulates transcription via Sch9, Paf1 complex, Ccr4-Not complex, Hmo1, and others [71]. TORC1 also contributes to ribosome biogenesis and ribosomal protein production by phosphorylating Sch9, which phosphorylates RiBi/RP repressors, activating RiBi/RP gene expression [182]. Ifh1 is phosphorylated by Casein Kinase 2 (CK2), a downstream effector of TOR, and interacts with Rap1-Fhl1 to drive RP/RiBi gene expression [183]. Other TORC1-dependent factors involved in RNA Pol II transcription include Hmo1, Abf1, and Sfp1 [183]. Lastly, TORC1 facilitates RNA Pol III-mediated transcription of small non-coding RNAs such as tRNAs by phosphorylating Sch9, thus activating TFIIIC subunit Bdp1 [184,185]. TORC1 also phosphorylates Maf1 on chromatin, like CK2, thus preventing Maf1 from interacting with RNA Pol III and modulating Maf1 nuclear export via Msn5 [184]. TORC1 integrates nutrient signaling with transcriptional regulation across all three RNA polymerases to support ribosome biogenesis and cellular growth. Additionally, cytoplasmic TORC1 plays a role in modulating RP/RiBi mRNA translation. Solid lines indicate a direct interaction, and dotted lines indicate an indirect interaction, either from an unknown mechanism or other effectors. Proteins within gray dotted boxes (such as Sch9, Paf1 complex, Ccr4-Not complex, Hmo1; Abf1, Sfp1, Hmo1) indicate that all listed proteins have similar downstream effects, specifically rRNA synthesis and RP/RiBi gene expression, respectively.