Redox regulation of the stability of the SUMO protease SENP3 via interactions with CHIP and Hsp90

Abstract

Redox regulation of the stability of the SUMO protease SENP3 via interactions with CHIP and Hsp90SENP3 was recently implicated as redox sensor affecting hypoxia-inducible factor-1-dependent transcription under conditions of mild oxidative stress. In a novel mechanism, the chaperone Hsp90 selectively stabilizes oxidized SENP3 by protecting it from ubiquitination mediated by the co-chaperone CHIP.

The biphasic redox sensing of SENP3 accounts for the HIF-1 transcriptional activity shift by oxidative stress

“…We also found that this accumulation following a blockage of ubiquitination can be attributed to the oxidation of cysteines 243 or 274 within the redox sensing domain of SENP3; the mutants (C243S or C274S) in which these cysteines were replaced by serine, an amino acid residue non-responsive to ROS, failed to accumulate under stress [35] . Given that the SENP3 protein level was unchanged upon high stress as compared with low stress and that the enzymatic activity of SENP3, as represented by its substrate binding capacity, was lost only under high stress, we hypothesized that, whereas mild stress oxidizes cysteines 243 or 274 to induce SENP3 stabilization, severe stress might oxidize another cysteine and inactivate the enzymatic activity of SENP3, ie, its capacity to bind with its substrates.…”

“…Constructs and the site-mutagenesis RGS tagged SENP3, HA tagged SUMO3, SENP3 mutants C243S and C532A were previously used in our work [35] . The mutant C532S was generated by QuikChange lighting SiteDirected Mutagenesis Kit (Agilent Technology, Santa Clara, CA, USA) with previously used method [35] .…”

“…The mutant C532S was generated by QuikChange lighting SiteDirected Mutagenesis Kit (Agilent Technology, Santa Clara, CA, USA) with previously used method [35] .…”

A role for SUMOylation in snoRNP biogenesis revealed by quantitative proteomics

“…Interestingly, a recent report has shown that Hsp90 can stabilize SENP3 under mild oxidative stress by preventing its ubiquitination and subsequent degradation. 42 Given that one function of Hsp90 is as a snoRNP assembly factor, 43,44 this report provides another potential link between snoRNP biogenesis and SUMOylation.…”

Sumoylation fights “aggregopathies”

“…10 Pointing the same way, oxidative stress can activate the deconjugating SENP3 isopeptidase. 11 Therefore, it is tempting to speculate that deregulated sumoylation is part of a vicious cycle involving oxidative stress, reduced overall sumoylation with further enhanced aggregation-induced toxicity that may itself augment mitochondrial dysfunction and, thereby, oxidative stress.…”