Chemical proteomics reveals ADP-ribosylation of small GTPases during oxidative stress

Nature Chemical Biology
Nathan P WestcottHoward C Hang

Abstract

ADP-ribosylation is a post-translational modification that is known to be involved in cellular homeostasis and stress but has been challenging to analyze biochemically. To facilitate the detection of ADP-ribosylated proteins, we show that an alkyne-adenosine analog, N6-propargyl adenosine (N6pA), is metabolically incorporated in mammalian cells and enables fluorescence detection and proteomic analysis of ADP-ribosylated proteins. Notably, our analysis of N6pA-labeled proteins that are upregulated by oxidative stress revealed differential ADP-ribosylation of small GTPases. We discovered that oxidative stress induced ADP-ribosylation of Hras on Cys181 and Cys184 in the C-terminal hypervariable region, which are normally S-fatty-acylated. Downstream Hras signaling is impaired by ADP-ribosylation during oxidative stress, but is rescued by ADP-ribosyltransferase inhibitors. Our study demonstrates that ADP-ribosylation of small GTPases not only is mediated by bacterial toxins but is endogenously regulated in mammalian cells. N6pA provides a useful tool to characterize ADP-ribosylated proteins and their regulatory mechanisms in cells.

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Citations

Apr 7, 2017·The FEBS Journal·Luca PalazzoIvan Ahel
Nov 4, 2017·Critical Reviews in Biochemistry and Molecular Biology·Kerryanne CrawfordIvan Ahel
May 11, 2018·Proteomics·Megan H Wright
Jan 26, 2020·Nature Communications·Pavel KielkowskiStephan A Sieber
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Aug 10, 2020·Current Opinion in Chemical Biology·Katarzyna Radziwon, Amy M Weeks
Apr 4, 2021·Cells·Ann-Katrin Hopp, Michael O Hottiger
Aug 10, 2021·Trends in Biochemical Sciences·Kelsie M Rodriguez, Michael S Cohen
Jan 24, 2018·Analytical Chemistry·Alyssa GarabedianAlexandre A Shvartsburg
Feb 22, 2022·Angewandte Chemie·Maike LehnerAndreas Marx

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