RRC ID 80949
Author Ravi, Kumar A, Bhattacharyya S, Singh J.
Title Thiol reductive stress activates the hypoxia response pathway.
Journal EMBO J
Abstract Owing to their capability to disrupt the oxidative protein folding environment in the endoplasmic reticulum (ER), thiol antioxidants, such as dithiothreitol (DTT), are used as ER-specific stressors. We recently showed that thiol antioxidants modulate the methionine-homocysteine cycle by upregulating an S-adenosylmethionine-dependent methyltransferase, rips-1, in Caenorhabditis elegans. However, the changes in cellular physiology induced by thiol stress that modulate the methionine-homocysteine cycle remain uncharacterized. Here, using forward genetic screens in C. elegans, we discover that thiol stress enhances rips-1 expression via the hypoxia response pathway. We demonstrate that thiol stress activates the hypoxia response pathway. The activation of the hypoxia response pathway by thiol stress is conserved in human cells. The hypoxia response pathway enhances thiol toxicity via rips-1 expression and confers protection against thiol toxicity via rips-1-independent mechanisms. Finally, we show that DTT might activate the hypoxia response pathway by producing hydrogen sulfide. Our studies reveal an intriguing interaction between thiol-mediated reductive stress and the hypoxia response pathway and challenge the current model that thiol antioxidant DTT disrupts only the ER milieu in the cell.
Volume 42(22)
Pages e114093
Published 2023-11-15
DOI 10.15252/embj.2023114093
PMID 37902464
PMC PMC10646554
MeSH Animals Antioxidants Caenorhabditis elegans* / genetics Endoplasmic Reticulum* / metabolism Endoplasmic Reticulum Stress Homocysteine / metabolism Humans Hypoxia / genetics Hypoxia / metabolism Methionine / metabolism
C.elegans tm2482