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

Aymeric P. Bailly (Lead / Corresponding author), Aurelien Perrin, Marina Serrano-Macia, Chantal Maghames, Orsolya Leidecker, Helene Trauchessec, M. L. Martinez-Chantar, Anton Gartner, Dimitris P. Xirodimas (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

9 Citations (Scopus)
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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.

Original languageEnglish
Pages (from-to)212-224.e8
Number of pages21
JournalCell Reports
Volume29
Issue number1
Early online date1 Oct 2019
DOIs
Publication statusPublished - 1 Oct 2019

Keywords

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

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