Abstract
SummaryUbiquitin and ubiquitin-like chains are finely balanced by conjugating and de-conjugating enzymes. Alterations in this balance trigger the response to stress conditions and are often observed in pathologies. How such changes are detected is not well understood. We identify the HSP70 chaperone as a sensor of changes in the balance between mono- and poly-NEDDylation. Upon DNA damage, the induction of the de-NEDDylating enzyme NEDP1 restricts the formation of NEDD8 chains, mainly through lysines K11/K48. This promotes APAF1 oligomerization and apoptosis induction, a step that requires the HSP70 ATPase activity. HSP70 binds to NEDD8, and, in vitro, the conversion of NEDD8 chains into mono-NEDD8 stimulates HSP70 ATPase activity. This effect is independent of NEDD8 conjugation onto substrates. The study indicates that the NEDD8 cycle is a regulatory module of HSP70 function. These findings may be important in tumorigenesis, as we find decreased NEDP1 levels in hepatocellular carcinoma with concomitant accumulation of NEDD8 conjugates.
Highlights
A key characteristic of ubiquitin and ubiquitin-like (Ubl) molecules is their ability to modify substrates as single moieties or in the form of polymeric chains
The studies reveal that heat shock protein 70 (HSP70) is a sensor of changes in the NEDD8 cycle controlled by NEDP1. They provide mechanistic insights on the role of poly-NEDDylation restriction as an activation signal for HSP70 function and apoptosis induction upon DNA damage. These findings may be relevant in pathology, as we found that NEDP1 protein levels are downregulated in a mouse model system for hepatocellular carcinoma with concomitant accumulation of NEDD8 conjugates
Elegans We identified ulp-3 (Ubl protease-3, sequence Y48A5A.2, GenBank: NP_001023477.1) as the C. elegans homologous gene of human NEDP1 by reciprocal BLAST analysis (Figure 1A)
Summary
A key characteristic of ubiquitin and ubiquitin-like (Ubl) molecules is their ability to modify substrates as single moieties or in the form of polymeric chains. The extent and topology of polymeric chains is finely balanced by the coordinated action of conjugating and de-conjugating enzymes (Williamson et al, 2013). The activity of these enzymes is altered as part of the cellular response to stress and is de-regulated in pathological conditions including cancer, immunological diseases, and neurodegenerative diseases (Popovic et al, 2014). These enzymes are regarded as major targets for therapeutic intervention. The pathways that sense such alterations are not well understood (Popovic et al, 2014; Williamson et al, 2013)
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