Abstract
Spatial management of stress-induced protein aggregation is an integral part of the proteostasis network. Protein modification by the ubiquitin-like molecule NEDD8 increases upon proteotoxic stress and it is characterised by the formation of hybrid NEDD8/ubiquitin conjugates. However, the biological significance of this response is unclear. Combination of quantitative proteomics with biological analysis shows that, during proteotoxic stress, NEDDylation promotes nuclear protein aggregation, including ribosomal proteins as a major group. This correlates with protection of the nuclear Ubiquitin Proteasome System from stress-induced dysfunction. Correspondingly, we show that NEDD8 compromises ubiquitination and prevents targeting and processing of substrates by the proteasome. Moreover, we identify HUWE1 as a key E3-ligase that is specifically required for NEDDylation during proteotoxic stress. The study reveals a specific role for NEDD8 in nuclear protein aggregation upon stress and is consistent with the concept that transient aggregate formation is part of a defence mechanism against proteotoxicity.
Highlights
Spatial management of stress-induced protein aggregation is an integral part of the proteostasis network
We report that NEDD8 promotes nuclear protein aggregation during proteotoxic stress and protects the nuclear Ubiquitin Proteasome System (UPS) from stress-induced dysfunction
Treatment of cells with the translational inhibitor Cycloheximide (CHX) prevented the increase in protein NEDDylation upon HS, indicating that the NEDD8 response to proteotoxic stress depends on protein synthesis (Fig. 1a)
Summary
Spatial management of stress-induced protein aggregation is an integral part of the proteostasis network. Combination of quantitative proteomics with biological analysis shows that, during proteotoxic stress, NEDDylation promotes nuclear protein aggregation, including ribosomal proteins as a major group This correlates with protection of the nuclear Ubiquitin Proteasome System from stress-induced dysfunction. The study reveals a specific role for NEDD8 in nuclear protein aggregation upon stress and is consistent with the concept that transient aggregate formation is part of a defence mechanism against proteotoxicity. The stress-induced NEDD8 conjugation depends on the ubiquitin E1-activating enzyme UBA1 and not on NAE This was quite surprising given the specificity of E1 enzymes in activating their cognate molecules[31]. NEDD8 compromises substrate ubiquitination and prevents their processing/degradation by the proteasome These effects are independent of NEDD8 activation by NAE and of the CRL function. This study identifies NEDDylation as a regulatory pathway of protein aggregation and UPS function in the nucleus during proteotoxic stress and is consistent with the concept that transient protein aggregation is a defence mechanism against proteotoxicity
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