The Balance between Mono- and NEDD8-Chains Controlled by NEDP1 upon DNA Damage Is a Regulatory Module of the HSP70 ATPase Activity
Summary: 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 chapero...
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doaj-9fa4ba19a00e48b0a7dfd1435cd673322020-11-25T02:09:26ZengElsevierCell Reports2211-12472019-10-01291212224.e8The Balance between Mono- and NEDD8-Chains Controlled by NEDP1 upon DNA Damage Is a Regulatory Module of the HSP70 ATPase ActivityAymeric P. Bailly0Aurelien Perrin1Marina Serrano-Macia2Chantal Maghames3Orsolya Leidecker4Helene Trauchessec5M.L. Martinez-Chantar6Anton Gartner7Dimitris P. Xirodimas8CRBM, CNRS, Univ. Montpellier, UMR5237, Montpellier 34090, Cedex 5, France; Corresponding authorCRBM, CNRS, Univ. Montpellier, UMR5237, Montpellier 34090, Cedex 5, FranceLiver Disease Laboratory, CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 48160 Derio, Bizkaia, SpainCRBM, CNRS, Univ. Montpellier, UMR5237, Montpellier 34090, Cedex 5, FranceCRBM, CNRS, Univ. Montpellier, UMR5237, Montpellier 34090, Cedex 5, FranceCRBM, CNRS, Univ. Montpellier, UMR5237, Montpellier 34090, Cedex 5, FranceLiver Disease Laboratory, CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 48160 Derio, Bizkaia, SpainCentre for Gene Regulation and Expression, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UKCRBM, CNRS, Univ. Montpellier, UMR5237, Montpellier 34090, Cedex 5, France; Corresponding authorSummary: 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. : The formation of ubiquitin and/or ubiquitin-like polymers is dynamically balanced by conjugating and de-conjugating enzymes. Bailly et al. report that the HSP70 chaperone is a sensor of the NEDD8 cycle. Conversion of NEDD8 chains into mono-NEDD8 by the de-NEDDylating enzyme NEDP1 upon DNA damage activates HSP70, which allows the formation of the apoptosome and apoptosis induction. Keywords: NEDD8, NEDP1/SENP8, C. elegans, HSP70, APAF1, DNA damage, apoptosis, proteomics, hepatocellular carcinoma, K11/K48 chainshttp://www.sciencedirect.com/science/article/pii/S2211124719311258 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Aymeric P. Bailly Aurelien Perrin Marina Serrano-Macia Chantal Maghames Orsolya Leidecker Helene Trauchessec M.L. Martinez-Chantar Anton Gartner Dimitris P. Xirodimas |
spellingShingle |
Aymeric P. Bailly Aurelien Perrin Marina Serrano-Macia Chantal Maghames Orsolya Leidecker Helene Trauchessec M.L. Martinez-Chantar Anton Gartner Dimitris P. Xirodimas The Balance between Mono- and NEDD8-Chains Controlled by NEDP1 upon DNA Damage Is a Regulatory Module of the HSP70 ATPase Activity Cell Reports |
author_facet |
Aymeric P. Bailly Aurelien Perrin Marina Serrano-Macia Chantal Maghames Orsolya Leidecker Helene Trauchessec M.L. Martinez-Chantar Anton Gartner Dimitris P. Xirodimas |
author_sort |
Aymeric P. Bailly |
title |
The Balance between Mono- and NEDD8-Chains Controlled by NEDP1 upon DNA Damage Is a Regulatory Module of the HSP70 ATPase Activity |
title_short |
The Balance between Mono- and NEDD8-Chains Controlled by NEDP1 upon DNA Damage Is a Regulatory Module of the HSP70 ATPase Activity |
title_full |
The Balance between Mono- and NEDD8-Chains Controlled by NEDP1 upon DNA Damage Is a Regulatory Module of the HSP70 ATPase Activity |
title_fullStr |
The Balance between Mono- and NEDD8-Chains Controlled by NEDP1 upon DNA Damage Is a Regulatory Module of the HSP70 ATPase Activity |
title_full_unstemmed |
The Balance between Mono- and NEDD8-Chains Controlled by NEDP1 upon DNA Damage Is a Regulatory Module of the HSP70 ATPase Activity |
title_sort |
balance between mono- and nedd8-chains controlled by nedp1 upon dna damage is a regulatory module of the hsp70 atpase activity |
publisher |
Elsevier |
series |
Cell Reports |
issn |
2211-1247 |
publishDate |
2019-10-01 |
description |
Summary: 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. : The formation of ubiquitin and/or ubiquitin-like polymers is dynamically balanced by conjugating and de-conjugating enzymes. Bailly et al. report that the HSP70 chaperone is a sensor of the NEDD8 cycle. Conversion of NEDD8 chains into mono-NEDD8 by the de-NEDDylating enzyme NEDP1 upon DNA damage activates HSP70, which allows the formation of the apoptosome and apoptosis induction. Keywords: NEDD8, NEDP1/SENP8, C. elegans, HSP70, APAF1, DNA damage, apoptosis, proteomics, hepatocellular carcinoma, K11/K48 chains |
url |
http://www.sciencedirect.com/science/article/pii/S2211124719311258 |
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