The Antioxidant Enzyme Methionine Sulfoxide Reductase A (MsrA) Interacts with Jab1/CSN5 and Regulates Its Function

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.

Controversies about selenium supplementation

“…SeIR plays an important role in aging mechanisms and neurological degeneration. Bacteria and yeast cells without the MSR gene show decreased tolerance or oxidative stress and shorter lifespans [22]. The overexpression of the MSRA in human T lymphocytes extends their lifespans in oxidative stress conditions.…”

Methionine Sulfoxide Speciation in Mouse Hippocampus Revealed by Global Proteomics Exhibits Age and Alzheimer’s Disease Dependent Changes Targeted to Mitochondrial and Glycolytic Pathways

“…Beyond these specific regulatory switches at a global level, methionine oxidation may act as a sensor of cellular stress [1,2,[16][17][18][19][20][21][22][23] where protein incorporated MSox is accumulated, depleted, and regulated by the inducible system of Msr or related enzymes. The biological effects of Msr variation by knockout or knock-in have showed lifespan variation in flies related to antioxidant defense but results in mouse were equivocal, showing tissue specific mouse functions affected [24].…”

Methionine Sulfoxide Speciation in Mouse Hippocampus Revealed by Global Proteomics Exhibits Age- and Alzheimer’s Disease-Dependent Changes Targeted to Mitochondrial and Glycolytic Pathways

“…Beyond these specific regulatory switches at a global level, methionine oxidation may act as a sensor of cellular stress [ 1 , 2 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ], where protein-incorporated MS ox is accumulated, depleted, and regulated by the inducible system of Msr or related enzymes. The biological effects of Msr variation by knock-out or knock-in have showed lifespan variation in flies related to antioxidant defense, but results in mouse were equivocal, showing tissue-specific mouse functions affected [ 24 ].…”