Unveiling mechanisms of translational control in disease

Abstract

<p dir="ltr">mRNA translation is a core cellular function that enables rapid alterations in proteome as a response to intra- or extracellular stimuli, with or without the corresponding changes in the transcriptome. Considering its prominent role in regulating numerous other cellular functions such as proliferation, metabolism, development, or stress response, its dysregulation contributes to the pathogenesis of multiple diseases.</p><p dir="ltr">Tuberous sclerosis complex (TSC) is an inherited multi-system disorder caused by loss-of-function mutations in TSC1 or TSC2 genes characterized by hyperactive mTOR signaling. In Study I, we characterized the alterations of gene expression programs caused by TSC1 loss-of-function mutations in neural progenitor cells (NPCs) that are also recapitulated in postmortem brains from autism spectrum disorder (ASD) donors. While rapamycin is the only approved therapy for TSC, we showed that it could not reverse the alterations caused by loss of TSC1 and rescue phenotypes such as neurite overgrowth. On the other hand, the bisteric mTORC1 inhibitor, RMC-6272, reversed the alterations of gene expression programs and rescued phenotypes associated with TSC1 loss. Overall, we provided a detailed overview of TSC1-dependent gene expression programs in NPCs that are recapitulated in postmortem ASD brains. In addition, we highlighted the potential of bi-steric mTORC1 inhibitors in treating TSC and associated phenotypes, offering a promising therapeutic avenue for TSC and related neurodevelopmental disorders.</p><p dir="ltr">The integrated stress response (ISR) enables the translation machinery to adjust to various stressors. In Study II, we present evidence of an osmoadaptation mechanism independent of the integrated stress response (ISR). This process involves reprogramming mRNA translation through the coordinated yet independent activities of the mTOR signaling and the plasma membrane amino acid transporter SNAT2. We revealed that the biphasic response to mild hyperosmotic stress involves a decrease in overall protein synthesis and mTOR signaling, followed by the translation of SNAT2. The induction of SNAT2 subsequently stimulates the intake of amino acids and restoration of mTOR activity and, thus, overall protein synthesis. This is accompanied by a partial reversal of the translation programs first affected by hyperosmotic stress during the early phase. Our results suggest that SNAT2 is a prominent mediator of osmoadaptation to mild hyperosmotic stress, serving as a molecular switch that controls the transition from inhibiting protein synthesis to establishing a biphasic osmoadaptive translation program.</p><p dir="ltr">Breast cancer, the most prevalent type of cancer in women, is a disease with a wide range of underlying molecular mechanisms. Tumor classification based on these molecular mechanisms is a crucial step that estimates disease progression and allows patients to benefit from currently available treatment methods. To date, efforts have been made to categorize tumors based on histological characteristics or gene expression programs; however, these methods do not consider mRNA translation as a means of tumor classification. In Study III, we used a data set of transcriptome-wide patterns of mRNA translation generated using patient tumors to investigate how mRNA translation is regulated in breast cancer patients. Moreover, our efforts helped us to identify mechanisms that, when combined, explain a large proportion of variation in mRNA translation in individual patients. Future studies will assess if identifying and targeting these translation mechanisms could serve as an opportunity for personalized cancer treatment.</p><h3>List of scientific papers</h3><p dir="ltr">I. Translatome analysis of tuberous sclerosis complex 1 patient-derived neural progenitor cells reveals rapamycin-dependent and independent alterations. <b>Aksoylu IS</b>, Martin P, Robert F, Szkop KJ, Redmond NE, Bhattacharyya S, Wang J, Chen S, Beauchamp RL, Nobeli I, Pelletier J, Larsson O, Ramesh V. Mol Autism. 2023 Oct 25;14(1):39. <br><a href="https://doi.org/10.1186/s13229-023-00572-3">https://doi.org/10.1186/s13229-023-00572-3<br></a><br></p><p dir="ltr">II. Stress-induced perturbations in intracellular amino acids reprogram mRNA translation in osmoadaptation independently of the ISR. Krokowski D, Jobava R, Szkop KJ, Chen CW, Fu X, Venus S, Guan BJ, Wu J, Gao Z, Banaszuk W, Tchorzewski M, Mu T, Ropelewski P, Merrick WC, Mao Y, <b>Aksoylu IS</b>, Miranda H, Qian SB, Manifava M, Ktistakis NT, Vourekas A, Jankowsky E, Topisirovic I, Larsson O, Hatzoglou M. Cell Rep. 2022 Jul 19;40(3):111092.<br><a href="https://doi.org/10.1016/j.celrep.2022.11109">https://doi.org/10.1016/j.celrep.2022.11109<br></a><br></p><p dir="ltr">III. Transcriptome-wide alterations in mRNA translation define breast cancer subtypes. <b>Aksoylu IS</b>, Bellato HM, Liang S, Lupinacci FCS, Masvidal-Sanz L, Oertlin C, Hajj GNM, Larsson O. [Manuscript]</p>