Stress-induced perturbations in intracellular amino acids reprogram mRNA translation in osmoadaptation independently of the ISR.

Phil Ropelewski, Maria Hatzoglou, Ola Larsson, Ivan Topisirovic, Eckhard Jankowsky, Anastasios Vourekas, Nicholas T Ktistakis, Maria Manifava, Shu-Bing Qian, Helen Miranda, Aksoylu Inci Sevval, Yuanhui Mao, William C Merrick, Dawid Krokowski, Tingwei Mu, Marek Tchorzewski, Wioleta Banaszuk, Zhaofeng Gao, Jing Wu, Bo-Jhih Guan, Sarah Venus, Xu Fu, Chien-Wen Chen, Krzysztof J Szkop, Raul Jobava

Journal: Cell reports 2022;40(3):111092

PMID: 35858571

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Abstract

The integrated stress response (ISR) plays a pivotal role in adaptation of translation machinery to cellular stress. Here, we demonstrate an ISR-independent osmoadaptation mechanism involving reprogramming of translation via coordinated but independent actions of mTOR and plasma membrane amino acid transporter SNAT2. This biphasic response entails reduced global protein synthesis and mTOR signaling followed by translation of SNAT2. Induction of SNAT2 leads to accumulation of amino acids and reactivation of mTOR and global protein synthesis, paralleled by partial reversal of the early-phase, stress-induced translatome. We propose SNAT2 functions as a molecular switch between inhibition of protein synthesis and establishment of an osmoadaptive translation program involving the formation of cytoplasmic condensates of SNAT2-regulated RNA-binding proteins DDX3X and FUS. In summary, we define key roles of SNAT2 in osmotolerance.

Address: Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA; Department of Molecular Biology, Institute of Biological Sciences, Maria Curie-Skłodowska University, Lublin, Poland. Electronic address: [email protected].; Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA; Department of Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.; Department of Oncology-Pathology, Science for Life Laboratories, Karolinska Institute, Stockholm, Sweden.; Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.; Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.; Department of Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.; Department of Molecular Biology, Institute of Biological Sciences, Maria Curie-Skłodowska University, Lublin, Poland.; Department of Molecular Biology, Institute of Biological Sciences, Maria Curie-Skłodowska University, Lublin, Poland; EcoTech-Complex Centre, Maria Curie-Skłodowska University, Lublin, Poland.; Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA.; Signalling Programme, Babraham Institute, Cambridge, UK.; Department of Biological Sciences, Louisiana State University, Baton Rouge, LA 70803, USA.; The Lady Davis Institute, Jewish General Hospital, Montréal, QC, Canada; Gerald Bronfman Department of Oncology, McGill University, Montréal, QC, Canada; Department of Biochemistry and Division of Experimental Medicine, McGill University, Montréal, QC, Canada. Electronic address: [email protected].; Department of Oncology-Pathology, Science for Life Laboratories, Karolinska Institute, Stockholm, Sweden. Electronic address: [email protected].; Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA. Electronic address: [email protected].

DOI: 10.1016/j.celrep.2022.111092