Methionine sulfoxide reductase A (MsrA) mediates the ubiquitination of 14-3-3 protein isotypes in brain

Abstract

The methionine sulfoxide reductase (Msr) system is known for its function in reducing protein-methionine sulfoxide to methionine. Recently, we showed that one member of the Msr system, MsrA, is involved in the ubiquitination-like process in Archaea. Here, the mammalian MsrA is demonstrated to mediate the ubiquitination of the 14-3-3 zeta protein and to promote the binding of 14-3-3 proteins to alpha synuclein in brain. MsrA was also found to enhance the ubiquitination and phosphorylation of Ser129 of alpha synuclein in brain. Furthermore, we demonstrate that, similarly to the archaeal MsrA, the mammalian MsrA can compete for capturing ubiquitin using the same active site it contains for methionine sulfoxide binding. Based on our previous observations showing that MsrA knockout mice have elevated expression levels of dopamine and 14-3-3 zeta and our current data, we propose that MsrA-dependent 14-3-3 zeta ubiquitination affects the regulation of alpha synuclein degradation and dopamine synthesis in the brain.

The Functions of the Mammalian Methionine Sulfoxide Reductase System and Related Diseases

“…This novel feature of MSRA suggests a dual function for this enzyme that is supposed to determine whether to repair or to degrade an oxidized protein. Recently, we have discovered that MSRA is involved in the ubiquitination of 14-3-3 proteins in the mouse brain [ 54 ]. This observation hints at the role of MSRA in protein degradation through the ubiquitin system.…”

Methionine Sulfoxide Reductases of Archaea

“…The finding that TafRMSR and MSRB-type MTH711 use an active site Cys A that is reduced by an external thiol and not a Cys R suggests that archaea use a streamlined mechanism for resolving the active site. The most recent finding—that H. volcanii MSRA has a moonlighting function in Ubl modification—is also surprising and helped guide the insight that MSRA competes for capturing ubiquitin and promotes ubiquitination in mammals [ 76 ]. Whether archaeal MSR enzymes can extend the lifespan of an organism remains to be determined.…”

Akt Phosphorylates NQO1 and Triggers its Degradation, Abolishing Its Antioxidative Activities in Parkinson's Disease

“…1, 2). The 14-3-3, an adaptor protein coupling Akt and its phosphorylation substrates, can be ubiquitinated by mammalian MrsA in the neurons (Deng et al, 2018). Presumably, 14-3-3 may involve in the interaction between Akt/ p-NQO1, mediating NQO1 polyubiquitination and degradation.…”