Arsenic toxicity to Saccharomyces cerevisiae is a consequence of inhibition of the TORC1 kinase combined with a chronic stress response.
The conserved Target Of Rapamycin (TOR) growth control signaling pathway is a major regulator of genes required for protein synthesis. The ubiquitous toxic metalloid arsenic, as well as mercury and nickel, are shown here to efficiently inhibit the rapamycin-sensitive TORC1 (TOR complex 1) protein kinase. This rapid inhibition of the TORC1 kinase is demonstrated in vivo by the dephosphorylation and inactivation of its downstream effector, the yeast S6 kinase homolog Sch9. Arsenic, mercury, and nickel cause reduction of transcription of ribosome biogenesis genes, which are under the control of Sfp1, a TORC1-regulated transcriptional activator. We report that arsenic stress deactivates Sfp1 as it becomes dephosphorylated, dissociates from chromatin, and exits the nucleus. Curiously, whereas loss of SFP1 function leads to increased arsenic resistance, absence of TOR1 or SCH9 has the opposite effect suggesting that TORC1 has a role beyond down-regulation of Sfp1. Indeed, we show that arsenic activates the transcription factors Msn2 and Msn4 both of which are targets of TORC1 and protein kinase A (PKA). In contrast to TORC1, PKA activity is not repressed during acute arsenic stress. A normal level of PKA activity might serve to dampen the stress response since hyperactive Msn2 will decrease arsenic tolerance. Thus arsenic toxicity in yeast might be determined by the balance between chronic activation of general stress factors in combination with lowered TORC1 kinase activity.
Hosiner
Dagmar
D
Department of Genetics, Max F. Perutz Laboratories, University of Vienna, A-1030 Vienna, Austria.
Lempiäinen
Harri
H
Reiter
Wolfgang
W
Urban
Joerg
J
Loewith
Robbie
R
Ammerer
Gustav
G
Schweyen
Rudolf
R
Shore
David
D
Schüller
Christoph
C
D001151:Arsenic / Q000633:toxicity*; D001483:Base Sequence; D002843:Chromatin / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects; D008954:Models, Biological; D008969:Molecular Sequence Data; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological / Q000187:drug effects*; D014158:Transcription, Genetic / Q000187:drug effects
D002843:Chromatin; D012333:RNA, Messenger; D029701:Saccharomyces cerevisiae Proteins; D011494:Protein Kinases; D001151:Arsenic