SUMOylation of ERp44 enhances Ero1α ER retention contributing to the pathogenesis of obesity and insulin resistance.

As the only E2 conjugating enzyme for the SUMO system, Ubc9-mediated SUMOylation has been recognized to regulate diverse biological processes, but its impact on adipocytes relevant to obesity and insulin resistance is yet to be elucidated. We established adipocyte-specific Ubc9 deficient mice to explore the effects of Ubc9 on obesity and metabolic disorders induced by high-fat diet (HFD) in adult mice. The molecular targets of SUMOylation were explored by liquid chromatography-mass spectrometry, and the regulatory mechanism of SUMOylation in T2D was analyzed. Adipocyte-specific depletion of Ubc9 (AdipoQ-Cre-Ubc9 ^fl/fl , Ubc9 ^AKO ) protected mice from HFD-induced obesity, insulin resistance, and hepatosteatosis. The Ubc9 ^AKO mice were featured by the reduced HFD-induced endoplasmic reticulum (ER) stress and inflammatory response. Mechanically, over nutrition rendered adipocytes to undergo a SUMOylation turnover characterized by the change of SUMOylation levels and substrates. ERp44 displayed the highest change in terms of SUMOylation levels of substrates involved in ER-related functions. The lack of ERp44 SUMOylation at lysine 76 (K76) located within the thioredoxin (TRX)-like domain by Ubc9 deficiency enhanced its degradation and suppressed its covalent binding to Ero1α, an oxidase that exists in the ER but lacks ER retention motif, thereby alleviating endoplasmic reticulum stress by promoting Ero1α secretion. Our data suggest that modulation of ERp44 SUMOylation in adipocytes could be a feasible strategy against obesity and insulin resistance in clinical settings. [Display omitted] • Ubc9 expression is upregulated in adipocyte during obese state. • Adipocyte-specific Ubc9 knockout ameliorates HFD-induced obesity and insulin resistance. • Ubc9-mediated ERp44 SUMOylation in K76 site exacerbates adipocyte ER stress and insulin resistance caused by lipotoxicity. • Disruption of ERp44 SUMOylation promotes Ero1α ER secretion, thereby attenuating lipotoxicity-induced ER stress. [ABSTRACT FROM AUTHOR]