Abstract
Hog1 is a mitogen-activated protein kinase in yeast that primarily regulates cellular responses to hyperosmolarity stress. In this study, we have examined the potential involvement of Hog1 in mediating cellular responses to DNA damaging agents. We find that treatment of yeast cells with DNA damaging agent methyl methanesulfonate (MMS) induces a marked and prolonged Hog1 activation. Distinct from stressors such as arsenite that activates Hog1 via inhibiting its phosphatases, activation of Hog1 by MMS is phosphatase-independent. Instead, MMS impairs a critical phosphor-relay process that normally keeps Hog1 in an inactive state. Functionally, MMS-activated Hog1 is not translocated to the nucleus to regulate gene expression but rather stays in the cytoplasm and regulates MMS-induced autophagy and cell adaptation to MMS stress. These findings reveal a new role of Hog1 in regulating MMS-induced cellular stress.
Highlights
Mitogen-activated protein kinases (MAPKs) are key components of cellular signaling pathways that allow eukaryotic cells to respond to a broad range of environmental signals
To examine if new protein synthesis of Hog1 protein induced by long term methyl methanesulfonate (MMS) treatment is responsible for the observed increase in phosphorylated Hog1, we examined the effect of MMS on Hog1 activation with or without the addition of protein synthesis inhibitor cycloheximide
We examined the involvement of Hog1, a mitogen-activated protein kinase, in cellular responses to DNA damaging agent MMS
Summary
Mitogen-activated protein kinases (MAPKs) are key components of cellular signaling pathways that allow eukaryotic cells to respond to a broad range of environmental signals. It has been shown that DNA damaging agents such as methyl methanesulfonate can activate Mpk1/Slt, a MAP kinase primarily responsible for cell wall maintenance (Soriano-Carot et al, 2012; Liu and Levin, 2018; Lee et al, 2019). Activation of Mpk1/Slt by methyl methanesulfonate is achieved via induced proteasomal degradation of Msg, a phosphatase that helps to maintain Mpk1/Slt at a low basal level of activation (Liu and Levin, 2018). Given that the basal level of Hog is maintained by its phosphatases (Lee and Levin, 2018), we became interested in if DNA damage could induce Hog activation by enhancing the degradation of its phosphatases. We find that the Sln branch of the HOG pathway is primarily responsible for mediating MMS-induced Hog activation
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