PT  - JOURNAL ARTICLE
AU  - Ajay Bhat
AU  - Rahul Chakraborty
AU  - Khushboo Adlakha
AU  - Ganesh Agam
AU  - Kausik Chakraborty
AU  - Shantanu Sengupta
TI  - Ncl1-mediated metabolic rewiring critical during metabolic stress
AID  - 10.26508/lsa.201900360
DP  - 2019 Aug 01
TA  - Life Science Alliance
PG  - e201900360
VI  - 2
IP  - 4
4099  - https://www.life-science-alliance.org/content/2/4/e201900360.short
4100  - https://www.life-science-alliance.org/content/2/4/e201900360.full
SO  - Life Sci. Alliance2019 Aug 01; 2
AB  - Nutritional limitation has been vastly studied; however, there is limited knowledge of how cells maintain homeostasis in excess nutrients. In this study, using yeast as a model system, we show that some amino acids are toxic at higher concentrations. With cysteine as a physiologically relevant example, we delineated the pathways/processes that are altered and those that are involved in survival in the presence of elevated levels of this amino acid. Using proteomics and metabolomics approach, we found that cysteine up-regulates proteins involved in amino acid metabolism, alters amino acid levels, and inhibits protein translation—events that are rescued by leucine supplementation. Through a comprehensive genetic screen, we show that leucine-mediated effect depends on a transfer RNA methyltransferase (NCL1), absence of which decouples transcription and translation in the cell, inhibits the conversion of leucine to ketoisocaproate, and leads to tricarboxylic acid cycle block. We therefore propose a role of NCL1 in regulating metabolic homeostasis through translational control.