Abstract
Methionine sulfoxide reductase A (MSRA) protects proteins from oxidation, and also helps remove reactive oxygen species (ROS) by recovering antioxidant enzymes inactivated by oxidation. Although its functions have been investigated extensively, little is known about the mechanism by which MSRA is regulated. Arrest defective 1 (ARD1) is an enzyme that catalyzes not only N-terminal acetylation as a cotranslational modification but also lysine acetylation as a posttranslational modification. ARD1, which is expressed in most cell types, is believed to participate in diverse biological processes, but its roles are poorly understood. Given that MSRA was hunted in a yeast two-hybrid screen with ARD1 as the bait, we here investigated whether ARD1 is a novel regulator of MSRA. ARD1 was shown to interact with and acetylate MSRA in both cells and test tubes. It specifically acetylated the K49 residue of MSRA, and by doing so repressed the enzymatic function of MSRA. ARD1 increased cellular levels of ROS, carbonylated proteins and DNA breaks under oxidative stress. Moreover, it promoted cell death induced by pro-oxidants, which was attenuated in MSRA-deficient cells. When mice were exposed to hyperoxic conditions for 2 days, their livers and kidneys were injured and protein carbonylation was increased. The oxidative tissue injury was more severe in ARD1 transgenic mice than in their wild-type littermates. In conclusion, ARD1 has a crucial role in the cellular response to oxidative stress as a bona fide regulator of MSRA. ARD1 is a potential target for ameliorating oxidative injury or for potentiating ROS-producing anticancer agents.
Highlights
The sulfur atom of methionine is oxidized by reactive oxygen species (ROS), with methionine being modified to methionine sulfoxide (MetO), which forms two enantiomers (S-sulfoxide and R-sulfoxide).[10]
Given that methionine sulfoxide reductase A (MSRA) was hunted with the bait Arrest defective 1 (ARD1) in the yeast two-hybrid screen, we began to explore a new role of ARD1 as an upstream regulator of MSRA
Cell-based and in vitro data strongly indicate that ARD1 directly binds to MSRA, acetylates it at K49 and inhibits its enzymatic function
Summary
The sulfur atom of methionine is oxidized by ROS, with methionine being modified to methionine sulfoxide (MetO), which forms two enantiomers (S-sulfoxide and R-sulfoxide).[10]. As MetO causes serious problems in life, the defense systems against MetO have been evolutionally conserved in prokaryotic and eukaryotic cells.[13] One such system, methionine sulfoxide reductase (MSR), has a crucial role in preventing the accumulation of MetO, and includes two enzymes, methionine sulfoxide reductase A (MSRA) and MSRB, which reduce S-sulfoxide and R-sulfoxide, respectively.[14]. N-terminal acetylation of nascent peptides as a cotranslational modification and lysine acetylation as a posttranslational modification.[15] In yeast and mammalian cells, ARD1 is known to have essential roles in cell growth and differentiation.[16,17]. ARD1 has been reported to control cell migration by acetylating myosin light chain kinase[18] and to promote cancer growth by acetylating β-catenin or the androgen receptor.[19] Considering that ARD1 is widely expressed in most mammalian cells,[20] it is expected that ARD1 has diverse functions beyond those mentioned above. To further understand the functions of ARD1, we sought novel targets of ARD1 using the yeast two-hybrid method and identified MSRA as an ARD1-
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