Cu/Zn Superoxide Dismutase (Sod1) regulates the canonical Wnt signaling pathway.

Cu/Zn Superoxide Dismutase (Sod1) catalyzes the disproportionation of cytotoxic superoxide radicals (O2•-) into oxygen (O2) and hydrogen peroxide (H2O2), a key signaling molecule. In Saccharomyces cerevisiae, we previously discovered that Sod1 participates in an H2O2-mediated redox signaling circuit that links nutrient availability to the control of energy metabolism. In response to glucose and O2, Sod1-derived H2O2 stabilizes a pair of conserved plasma membrane kinases - yeast casein kinase 1 and 2 (Yck1/2) - that signal glycolytic growth and the repression of respiration. The Yck1/2 homolog in humans, casein kinase 1-γ (CK1γ), is an integral component of the Wingless and Int-1 (Wnt) signaling pathway, which is essential for regulating cell fate and proliferation in early development and adult tissue and is dysregulated in many cancers. Herein, we establish the conservation of the SOD1/YCK1 redox signaling axis in humans by finding that SOD1 regulates CK1γ expression in human embryonic kidney 293 (HEK293) cells and is required for canonical Wnt signaling and Wnt-dependent cell proliferation.

Extra-mitochondrial Cu/Zn superoxide dismutase (Sod1) is dispensable for protection against oxidative stress but mediates peroxide signaling in Saccharomyces cerevisiae.

Cu/Zn Superoxide Dismutase (Sod1) is a highly conserved and abundant metalloenzyme that catalyzes the disproportionation of superoxide radicals into hydrogen peroxide and molecular oxygen. As a consequence, Sod1 serves dual roles in oxidative stress protection and redox signaling by both scavenging cytotoxic superoxide radicals and producing hydrogen peroxide that can be used to oxidize and regulate the activity of downstream targets. However, the relative contributions of Sod1 to protection against oxidative stress and redox signaling are poorly understood. Using the model unicellular eukaryote, Baker's yeast, we found that only a small fraction of the total Sod1 pool is required for protection against superoxide toxicity and that this pool is localized to the mitochondrial intermembrane space. On the contrary, we find that much larger amounts of extra-mitochondrial Sod1 are critical for peroxide-mediated redox signaling. Altogether, our results force the re-evaluation of the physiological role of bulk Sod1 in redox biology; namely, we propose that the vast majority of Sod1 in yeast is utilized for peroxide-mediated signaling rather than superoxide scavenging.