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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.
Pubmed ID: 31577950
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View all literature mentionsPrivately held company that develops and produces antibodies, ELISA kits, ChIP kits, proteomic kits, and other related reagents used to study cell signaling pathways that impact human health.
View all literature mentionsCell line U2OS is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line NCI-H1299 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line MCF-7 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsThis monoclonal targets NEDD8 (N-term) [Y297] antibody
View all literature mentionsThis monoclonal targets Cullin 1
View all literature mentionsThis monoclonal targets Hsp70 antibody [C92F3A-5]
View all literature mentionsThis monoclonal targets APAF1
View all literature mentionsThis monoclonal targets alpha-Tubulin (DM1A) Mouse mAb
View all literature mentionsThis unknown targets ANTI-FLAG(R) M2 Affinity Gel
View all literature mentionsThis polyclonal targets Human Cullin 4a
View all literature mentionsThis polyclonal targets Histone H2A
View all literature mentionsThis polyclonal targets Histone H2A.X
View all literature mentionsThis monoclonal targets Apaf-1
View all literature mentionsThis monoclonal targets GAPDH antibody [6C5]
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