Stepwise phosphorylation and SUMOylation of PIDD1 drive PIDDosome assembly in response to DNA repair failure.


Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
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

9195

Subventions

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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Auteurs

Richa B Shah (RB)

Department of Medicine, Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Cell, Developmental and Regenerative Biology, The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Yuanyuan Li (Y)

Department of Medicine, Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Cell, Developmental and Regenerative Biology, The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Honglin Yu (H)

Department of Medicine, Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Cell, Developmental and Regenerative Biology, The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Ela Kini (E)

Department of Medicine, Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Department of Cell, Developmental and Regenerative Biology, The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Samuel Sidi (S)

Department of Medicine, Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. samuel.sidi@mssm.edu.
Department of Cell, Developmental and Regenerative Biology, The Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. samuel.sidi@mssm.edu.
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. samuel.sidi@mssm.edu.

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