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Cell Rep. 2019 Oct 1;29(1):212-224.e8. doi: 10.1016/j.celrep.2019.08.070.

The Balance between Mono- and NEDD8-Chains Controlled by NEDP1 upon DNA Damage Is a Regulatory Module of the HSP70 ATPase Activity.

Author information

1
CRBM, CNRS, Univ. Montpellier, UMR5237, Montpellier 34090, Cedex 5, France. Electronic address: aymeric.bailly@crbm.cnrs.fr.
2
CRBM, CNRS, Univ. Montpellier, UMR5237, Montpellier 34090, Cedex 5, France.
3
Liver Disease Laboratory, CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 48160 Derio, Bizkaia, Spain.
4
Centre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK.
5
CRBM, CNRS, Univ. Montpellier, UMR5237, Montpellier 34090, Cedex 5, France. Electronic address: dimitris.xirodimas@crbm.cnrs.fr.

Abstract

Ubiquitin 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.

KEYWORDS:

APAF1; C. elegans; DNA damage; HSP70; K11/K48 chains; NEDD8; NEDP1/SENP8; apoptosis; hepatocellular carcinoma; proteomics

PMID:
31577950
DOI:
10.1016/j.celrep.2019.08.070
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