Lithium Chloride Sensitivity in Yeast and Regulation of Translation

Abstract

For decades, lithium chloride (LiCl) has been used as a treatment option for those living with bipolar disorder (BD). As a result, many studies have been conducted to examine its mode of action, toxicity, and downstream cellular responses. We know that LiCl is able to affect cell signaling and signaling transduction pathways through protein kinase C and glycogen synthase kinase-3, which are considered to be important in regulating gene expression at the translational level. However, additional downstream effects require further investigation, especially in translation pathway. In yeast, LiCl treatment affects the expression, and thus the activity, of PGM2, a phosphoglucomutase involved in sugar metabolism. Inhibition of PGM2 leads to the accumulation of intermediate metabolites of galactose metabolism causing cell toxicity. However, it is not fully understood how LiCl affects gene expression in this matter. In this study, we identified three genes, NAM7, PUS2, and RPL27B, which increase yeast LiCl sensitivity when deleted. We further demonstrate that NAM7, PUS2, and RPL27B influence translation and exert their activity through the 5′-Untranslated region (5′-UTR) of PGM2 mRNA in yeast.

Lithium Chloride Sensitivity Connects the Activity of PEX11 and RIM20 to PGM2 translation

“…Overexpression of eIF4A is shown to recover sensitivity of the yeast cells to LiCl in galactose media. Similar observation has also been reported for other genes linked to the translation of structured mRNAs in yeast [15,16]. Deletion mutants for these genes showed increased sensitivity to LiCl.…”

“…In the literature the molecular activities for PEX11 and RIM20 have not been linked to LiCl sensitivity making these genes intriguing target for further study. LiCl toxicity in yeast is thought to be caused by the accumulation of galactose intermediate metabolites, particularly galactose-1p [14,15]. It has been shown that LiCl inhibits the conversion of glucose-1-phosphate to glucose-6-phosphate via modifying the expression of the phosphoglucomutase enzyme PGM2 [11].…”

“…Similar observations were made using other mRNAs with various 5'-UTRs that carry different structures, but not for the ones without. We recently reported on the nding of several additional genes involved in the translation of structured mRNAs, [15,16]. The identi cation of new gene functions that in uences the translation of structured mRNAs suggests that translation of mRNAs with structures seems to be more complex than what was originally thought.…”

“…Due to the reduced tness of double mutant this type of interaction is called negative genetic interaction (nGI). Many studies use nGIs to investigate gene function and pathway interactions [15,16,29,37].…”

DBP7 and YRF1-6 Are Involved in Cell Sensitivity to LiCl by Regulating the Translation of PGM2 mRNA

“…eIF4A has been implicated in yeast’s response to LiCl stress [ 8 ]. Overexpression of eIF4A has been found to restore yeast cell sensitivity to LiCl in a galactose medium [ 13 , 14 ].…”