Stabilization of the methyl-CpG binding protein ZBTB38 by the deubiquitinase USP9X limits the occurrence and toxicity of oxidative stress in human cells

Nucleic Acids Research
Benoit MiottoPierre-Antoine Defossez

Abstract

Reactive oxygen species (ROS) are a byproduct of cell metabolism, and can also arise from environmental sources, such as toxins or radiation. Depending on dose and context, ROS have both beneficial and deleterious roles in mammalian development and disease, therefore it is crucial to understand how these molecules are generated, sensed, and detoxified. The question of how oxidative stress connects to the epigenome, in particular, is important yet incompletely understood. Here we show that an epigenetic regulator, the methyl-CpG-binding protein ZBTB38, limits the basal cellular production of ROS, is induced by ROS, and is required to mount a proper response to oxidative stress. Molecularly, these functions depend on a deubiquitinase, USP9X, which interacts with ZBTB38, deubiquitinates it, and stabilizes it. We find that USP9X is itself stabilized by oxidative stress, and is required together with ZBTB38 to limit the basal generation of ROS, as well as the toxicity of an acute oxidative stress. Our data uncover a new nuclear target of USP9X, show that the USP9X/ZBTB38 axis limits, senses and detoxifies ROS, and provide a molecular link between oxidative stress and the epigenome.

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Citations

Feb 2, 2019·Current Protocols in Protein Science·Guillaume AdelmantJarrod A Marto
May 6, 2020·Cancers·Maud de DieuleveultBenoit Miotto
Sep 22, 2020·PloS One·Rachel Wong, Deepta Bhattacharya
Jan 23, 2020·Journal of Cell Science·Rachel O'Dea, Corrado Santocanale
Oct 20, 2019·Journal of Molecular Biology·Amelia J HodgesBethany A Buck-Koehntop
May 7, 2019·Journal of Proteome Research·Xiangling ChenHu Zhou

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Methods Mentioned

BETA
PCR
co-immunoprecipitation
proximity ligation
pull-down
electrophoresis
FACS
affinity purification
immunoprecipitation
immunoprecipitations
Assay

Software Mentioned

CellQuest Pro
Mascot
BD
[UNK] Pro
multiplierz scripts

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