Abstract
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.
Highlights
Cell requires optimal amount of nutrients for the synthesis of macromolecules like lipid, protein, and nucleotides
We show that a transfer RNA methyltransferase (NCL1) is involved in survival during cysteine stress, absence of which inhibited the conversion of leucine to ketoisocaproate (KIC)—a necessary step for mitigating the effect of cysteine
Cysteine increases the levels of lysine and decreases the levels of threonine, and as a consequence, the expression of enzymes required for their biosynthesis is altered in opposite directions
Summary
Cell requires optimal amount of nutrients for the synthesis of macromolecules like lipid, protein, and nucleotides. Activation of these anabolic processes and the repression of catabolic processes like autophagy promote cellular growth. When nutrients are limiting, anabolic processes are inhibited, and autophagy is activated [1]. Among these processes, protein synthesis consumes a large portion of nutrients and energy [2, 3]. Limitation of amino acids promotes Gcn2-mediated signaling [9] and inhibits TORC1 [10], both of which lead to inhibition of protein synthesis [1, 11]
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