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Methionine sulfoxide reductase B3 (MsrB3) is an oxidoreductase in the endoplasmic reticulum that catalyzes the stereospecific reduction of methionine-R-sulfoxide to methionine. Here, we report the critical role and mechanisms of MsrB3 in cell proliferation. The deletion of MsrB3 led to a significant decrease in cell proliferation in mouse embryonic fibroblast (MEF) cells. MsrB3-knockout MEF cells showed increased p53 protein levels, compared to wild-type MEF cells, which subsequently elevated the protein level of cyclin-dependent kinase inhibitor p21. In addition, MsrB3 deficiency enhanced the protein level of p27, another cell cycle regulator, and caused cell cycle arrest at the G1 stage. The inhibitory effect of MsrB3 deficiency on cell proliferation through the activation of p53-p21 and p27 pathways was also confirmed in primary human dermal fibroblasts. Collectively, the data suggest that MsrB3 is a regulator of cell growth through the p53-p21 and p27 pathways.

Methionine sulfoxide reductase A (MsrA) functions as a protein repair enzyme by catalyzing the stereospecific reduction of methionine-S-sulfoxide to methionine. We previously identified that MsrA deficiency inhibits normal cell growth via activation of the p53–p21 pathway. In this study, we report a critical role of MsrA in expression of heme oxygenase-1 (HO-1), a highly inducible enzyme that has an anti-proliferative effect mediated by up-regulation of p21. Down-regulation of MsrA induced HO-1 expression in mammalian cells with increased p21 levels, but MsrA overexpression did not affect HO-1 expression. MsrA depletion activated Nrf2 by increasing its expression and nuclear translocation. Nrf2 activation was associated with increased reactive oxygen species production. MsrA overexpression in MsrA-depleted cells led to the reduction of increased HO-1 expression, and suppressed nuclear accumulation of Nrf2. Taken together, the data suggest that MsrA attenuates HO-1 induction by inhibiting Nrf2 activation.