SOD1 Phosphorylation by mTORC1 Couples Nutrient Sensing and Redox Regulation

Chi Kwan Tsang; Miao Chen; Xin Cheng; Yanmei Qi; Yin Chen; Ishani Das; Xiaoxing Li; Brinda Vallat; Li-Wu Fu; Chao-Nan Qian; Hui-Yun Wang; Eileen White; Stephen K Burley; X F Steven Zheng

doi:10.1016/j.molcel.2018.03.029

SOD1 Phosphorylation by mTORC1 Couples Nutrient Sensing and Redox Regulation

Mol Cell. 2018 May 3;70(3):502-515.e8. doi: 10.1016/j.molcel.2018.03.029.

Authors

Chi Kwan Tsang¹, Miao Chen², Xin Cheng³, Yanmei Qi³, Yin Chen², Ishani Das³, Xiaoxing Li², Brinda Vallat⁴, Li-Wu Fu², Chao-Nan Qian², Hui-Yun Wang⁵, Eileen White⁶, Stephen K Burley⁷, X F Steven Zheng⁸

Affiliations

¹ Rutgers Cancer Institute of New Jersey, Rutgers, State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA; Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers, State University of New Jersey, 675 Hoes Lane, Piscataway, NJ 08854, USA; Clinical Neuroscience Institute, The First Affiliated Hospital, Jinan University, 613 Huangpu Avenue West, Guangzhou, Guangdong 510632, China.
² State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China.
³ Rutgers Cancer Institute of New Jersey, Rutgers, State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA.
⁴ Institute for Quantitative Biomedicine and Department of Chemistry and Chemical Biology, Rutgers, State University of New Jersey, Piscataway, NJ 08854 USA.
⁵ Rutgers Cancer Institute of New Jersey, Rutgers, State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA; State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China; Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers, State University of New Jersey, 675 Hoes Lane, Piscataway, NJ 08854, USA.
⁶ Rutgers Cancer Institute of New Jersey, Rutgers, State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA; Department of Molecular Biology and Biochemistry, Rutgers, State University of New Jersey, 604 Allison Road, Piscataway, NJ 08854, USA.
⁷ Rutgers Cancer Institute of New Jersey, Rutgers, State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA; Institute for Quantitative Biomedicine and Department of Chemistry and Chemical Biology, Rutgers, State University of New Jersey, Piscataway, NJ 08854 USA.
⁸ Rutgers Cancer Institute of New Jersey, Rutgers, State University of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA; Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers, State University of New Jersey, 675 Hoes Lane, Piscataway, NJ 08854, USA. Electronic address: zhengst@cinj.rutgers.edu.

Abstract

Nutrients are not only organic compounds fueling bioenergetics and biosynthesis, but also key chemical signals controlling growth and metabolism. Nutrients enormously impact the production of reactive oxygen species (ROS), which play essential roles in normal physiology and diseases. How nutrient signaling is integrated with redox regulation is an interesting, but not fully understood, question. Herein, we report that superoxide dismutase 1 (SOD1) is a conserved component of the mechanistic target of rapamycin complex 1 (mTORC1) nutrient signaling. mTORC1 regulates SOD1 activity through reversible phosphorylation at S39 in yeast and T40 in humans in response to nutrients, which moderates ROS level and prevents oxidative DNA damage. We further show that SOD1 activation enhances cancer cell survival and tumor formation in the ischemic tumor microenvironment and protects against the chemotherapeutic agent cisplatin. Collectively, these findings identify a conserved mechanism by which eukaryotes dynamically regulate redox homeostasis in response to changing nutrient conditions.

Keywords: Warburg; cancer; cisplatin; ischemia; mTOR; nutrient; rapamycin; reactive oxygen species; redox; superoxide dismutase 1.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Cell Line
Cell Line, Tumor
DNA Damage / physiology
Energy Metabolism / physiology
Female
HEK293 Cells
Humans
MCF-7 Cells
Mechanistic Target of Rapamycin Complex 1 / metabolism*
Mice, Inbred BALB C
Mice, Nude
Nutrients / metabolism*
Oxidation-Reduction
Phosphorylation / physiology*
Reactive Oxygen Species / metabolism
Signal Transduction / physiology
Superoxide Dismutase-1 / metabolism*
TOR Serine-Threonine Kinases / metabolism

Substances

Reactive Oxygen Species
Superoxide Dismutase-1
Mechanistic Target of Rapamycin Complex 1
TOR Serine-Threonine Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding