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

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

  • Cell Rep. 2022 Jul 19;40(3):111092. doi: 10.1016/j.celrep.2022.111092.
Dawid Krokowski 1,  Raul Jobava 2,  Krzysztof J Szkop 3,  Chien-Wen Chen 4,  Xu Fu 5,  Sarah Venus 6,  Bo-Jhih Guan 4,  Jing Wu 4,  Zhaofeng Gao 4,  Wioleta Banaszuk 7,  Marek Tchorzewski 8,  Tingwei Mu 5,  Phil Ropelewski 5,  William C Merrick 6,  Yuanhui Mao 9,  Aksoylu Inci Sevval 3,  Helen Miranda 4,  Shu-Bing Qian 9,  Maria Manifava 10,  Nicholas T Ktistakis 10,  Anastasios Vourekas 11,  Eckhard Jankowsky 6,  Ivan Topisirovic 12,  Ola Larsson 13,  Maria Hatzoglou 14
Affiliations

Affiliations

  • 1 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: krokud@gmail.com.
  • 2 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.
  • 3 Department of Oncology-Pathology, Science for Life Laboratories, Karolinska Institute, Stockholm, Sweden.
  • 4 Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.
  • 5 Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.
  • 6 Department of Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.
  • 7 Department of Molecular Biology, Institute of Biological Sciences, Maria Curie-Skłodowska University, Lublin, Poland.
  • 8 Department of Molecular Biology, Institute of Biological Sciences, Maria Curie-Skłodowska University, Lublin, Poland; EcoTech-Complex Centre, Maria Curie-Skłodowska University, Lublin, Poland.
  • 9 Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA.
  • 10 Signalling Programme, Babraham Institute, Cambridge, UK.
  • 11 Department of Biological Sciences, Louisiana State University, Baton Rouge, LA 70803, USA.
  • 12 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: ivan.topisirovic@mcgill.ca.
  • 13 Department of Oncology-Pathology, Science for Life Laboratories, Karolinska Institute, Stockholm, Sweden. Electronic address: ola.larsson@ki.se.
  • 14 Department of Genetics and Genome Sciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA. Electronic address: mxh8@case.edu.
PMID: 35858571 DOI: 10.1016/j.celrep.2022.111092
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.

Keywords

CP: Molecular biology; amino acids; cytoplasmic condensates; hypertonic stress; mTOR signaling; osmolytes; osmotolerance; translation.

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