Stepwise phosphorylation and SUMOylation of PIDD1 drive PIDDosome assembly in response to DNA repair failure.
Sumoylation
Humans
Phosphorylation
DNA Repair
Protein Inhibitors of Activated STAT
/ metabolism
Cysteine Endopeptidases
/ metabolism
DNA Damage
Death Domain Receptor Signaling Adaptor Proteins
/ metabolism
Apoptosis
Caspase 2
/ metabolism
SUMO-1 Protein
/ metabolism
HEK293 Cells
HeLa Cells
Small Ubiquitin-Related Modifier Proteins
Ataxia Telangiectasia Mutated Proteins
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
24 Oct 2024
24 Oct 2024
Historique:
received:
05
06
2024
accepted:
08
10
2024
medline:
25
10
2024
pubmed:
25
10
2024
entrez:
25
10
2024
Statut:
epublish
Résumé
SUMOylation regulates numerous cellular stress responses, yet targets in the apoptotic machinery remain elusive. We show that a single, DNA damage-induced monoSUMOylation event controls PIDDosome (PIDD1/RAIDD/caspase-2) formation and apoptotic death in response to unresolved DNA interstrand crosslinks (ICLs). SUMO-1 conjugation occurs on conserved K879 in the PIDD1 death domain (DD); is catalyzed by PIAS1 and countered by SENP3; and is triggered by ATR phosphorylation of neighboring T788 in the PIDD1 DD, which enables PIAS1 docking. Phospho/SUMO-PIDD1 proteins are captured by nucleolar RAIDD monomers via a SUMO-interacting motif (SIM) in the RAIDD DD, thus compartmentalizing nascent PIDDosomes for caspase-2 recruitment. Denying SUMOylation or the SUMO-SIM interaction spares the onset of PIDDosome assembly but blocks its completion, thus eliminating the apoptotic response to ICL repair failure. Conversely, removal of SENP3 forces apoptosis, even in cells with tolerable ICL levels. SUMO-mediated PIDDosome control is also seen in response to DNA breaks but not supernumerary centrosomes. These results illuminate PIDDosome formation in space and time and identify a direct role for SUMOylation in the assembly of a major pro-apoptotic device.
Identifiants
pubmed: 39448602
doi: 10.1038/s41467-024-53412-0
pii: 10.1038/s41467-024-53412-0
doi:
Substances chimiques
PIDD1 protein, human
0
Protein Inhibitors of Activated STAT
0
Cysteine Endopeptidases
EC 3.4.22.-
Death Domain Receptor Signaling Adaptor Proteins
0
Caspase 2
EC 3.4.22.-
SENP3 protein, human
EC 3.4.22.-
SUMO-1 Protein
0
PIAS1 protein, human
0
ATR protein, human
EC 2.7.11.1
Small Ubiquitin-Related Modifier Proteins
0
Ataxia Telangiectasia Mutated Proteins
EC 2.7.11.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
9195Subventions
Organisme : U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
ID : R01CA178162
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)
ID : RO1GM135301
Informations de copyright
© 2024. The Author(s).
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