UBC9-associated SUMOylation contributes to β-catenin activation and kidney fibrosis

SUMOylation is a form of post-translational modification that conjugates a small ubiquitin-like modifier (SUMO) to specific lysine residues of target proteins. The role and regulation of SUMOylation in kidney physiology and pathogenesis are largely unknown. Here, we report that SUMOylation promotes kidney fibrosis by enhancing β-catenin signaling.

UBC9, the sole E2 conjugating enzyme in SUMOylation, was ablated from proximal tubules to determine the role of SUMOylation in mouse kidney fibrosis after obstructed nephropathy or ischemia-reperfusion injury. Point mutations were introduced to identify the SUMOylation sites in β-catenin.

UBC9 was induced in tissues from patients with obstructive or IgA nephropathies and in mouse fibrotic kidneys. Kidney fibrosis in mouse models was alleviated by pharmacological inhibitors of SUMOylation or by UBC9 knockout from kidney proximal tubules. Consistently, knockdown of UBC9 attenuated transforming growth factor-β-induced fibrotic changes in kidney tubular cells in vitro. Mechanistically, fibrotic stress increased the SUMOylation of β-catenin, which contributed to the stability and activation of β-catenin. We further identified three SUMOylation sites in β-catenin, the mutation of which reduced the stability and activation of β-catenin during fibrotic stress.

Our results unveil a novel role of SUMOylation in kidney fibrogenesis by activating β-catenin, suggesting a new anti-fibrosis strategy.