Abstract
Methionine sulfoxide (MetO) is an oxidative posttranslational modification that primarily occurs under oxidative stress conditions, leading to alteration of protein structure and function. This modification is regulated by MetO reduction through the evolutionarily conserved methionine sulfoxide reductase (Msr) system. The Msr type A enzyme (MsrA) plays an important role as a cellular antioxidant and promotes cell survival. The ubiquitin- (Ub) like neddylation pathway, which is controlled by the c-Jun activation domain-binding protein-1 (Jab1), also affects cell survival. Jab1 negatively regulates expression of the cell cycle inhibitor cyclin-dependent kinase inhibitor 1B (P27) through binding and targeting P27 for ubiquitination and degradation. Here we report the finding that MsrA interacts with Jab1 and enhances Jab1′s deneddylase activity (removal of Nedd8). In turn, an increase is observed in the level of deneddylated Cullin-1 (Cul-1, a component of E3 Ub ligase complexes). Furthermore, the action of MsrA increases the binding affinity of Jab1 to P27, while MsrA ablation causes a dramatic increase in P27 expression. Thus, an interaction between MsrA and Jab1 is proposed to have a positive effect on the function of Jab1 and to serve as a means to regulate cellular resistance to oxidative stress and to enhance cell survival.
Highlights
The methionine sulfoxide reductase (Msr) system consists of Msr type A (MsrA) and Msr type B (MsrB) that reduce S-Methionine sulfoxide (MetO) and R-MetO, respectively [1,2]
MsrA interacting proteins of the Homo sapiens proteome were identified by a yeast-two hybrid (Y2H) approach
The results showed that the presence/absence of support our hypothesis, that MsrA regulates Jun activation domain-binding protein-1 (Jab1) deneddylase activity through post-translational had no effect on the level ofreduction
Summary
The methionine sulfoxide reductase (Msr) system consists of Msr type A (MsrA) and Msr type B (MsrB) that reduce S-MetO and R-MetO, respectively [1,2]. Neddylation is a posttranslational modification system that adds the ubiquitin-like neural precursor cell expressed developmentally down-regulated 8 (Nedd8) to substrate proteins [16] (Figure 1). Removal of Nedd from proteins is mediated by c-Jun activation domain-binding protein-1 (Jab1) (synonym CSN5), which is the fifth subunit of the constitutive photomorphogenic-9 signalosome (COP9). Regulation of CRLs by the CSN involves the removal of Nedd from Cul-1, the cullin scaffold subunit of CRLs, through the hydrolytic activity of a metalloprotease MPN+/JAMM motif (the c-Jun binding domain) within the catalytic Jab subunit of CSN. The deneddylation of Cul-1 by the Jab active site of CSN acts as an upstream regulator of Skp1/Cul-1/F-box (SCF)-dependent ubiquitination of numerous substrates, including P27 and IκBα [32]. (Jab1)/Csn subunit active site of the COP9-signalosome, which cleaves the isopeptide linkage to release neural precursor cell expressed.
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