PIDD mediates NF-kappaB activation in response to DNA damage.
Activation of NF-kappaB following genotoxic stress allows time for DNA-damage repair and ensures cell survival accounting for acquired chemoresistance, an impediment to effective cancer therapy. Despite this clinical relevance, little is known about pathways that enable genotoxic-stress-induced NF-kappaB induction. Previously, we reported a role for the p53-inducible death-domain-containing protein, PIDD, in caspase-2 activation and apoptosis in response to DNA damage. We now demonstrate that PIDD plays a critical role in DNA-damage-induced NF-kappaB activation. Upon genotoxic stress, a complex between PIDD, the kinase RIP1, and a component of the NF-kappaB-activating kinase complex, NEMO, is formed. PIDD expression enhances genotoxic-stress-induced NF-kappaB activation through augmented sumoylation and ubiquitination of NEMO. Depletion of PIDD and RIP1, but not caspase-2, abrogates DNA-damage-induced NEMO modification and NF-kappaB activation. We propose that PIDD acts as a molecular switch, controlling the balance between life and death upon DNA damage.
Janssens
Sophie
S
Department of Biochemistry, University of Lausanne, BIL Biomedical Research Center, Chemin des Boveresses 155, CH-1066 Epalinges, Switzerland.
Tinel
Antoine
A
Lippens
Saskia
S
Tschopp
Jürg
J
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D001667:Binding, Competitive; D053420:CRADD Signaling Adaptor Protein; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D053143:Caspase 2; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage / Q000502:physiology*; D053418:Death Domain Receptor Signaling Adaptor Proteins; D004317:Doxorubicin / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D007038:Hypotonic Solutions / Q000494:pharmacology; D051550:I-kappa B Kinase / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D019169:Jurkat Cells; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D028861:Nuclear Pore Complex Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D021381:Protein Transport / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D025801:Ubiquitin / Q000378:metabolism; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
C119724:AGFG1 protein, human; D048868:Adaptor Proteins, Signal Transducing; C494811:BCL2L1 protein, human; D053420:CRADD Signaling Adaptor Protein; C104252:CRADD protein, human; D002352:Carrier Proteins; D053418:Death Domain Receptor Signaling Adaptor Proteins; D005231:Fatty Acids, Unsaturated; D007038:Hypotonic Solutions; D020672:I-kappa B Proteins; C491731:IKBKG protein, human; D016328:NF-kappa B; D028861:Nuclear Pore Complex Proteins; C485896:PIDD1 protein, human; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D025841:Small Ubiquitin-Related Modifier Proteins; D014409:Tumor Necrosis Factor-alpha; D025801:Ubiquitin; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D051020:bcl-X Protein; D005047:Etoposide; D004317:Doxorubicin; D004247:DNA; D051550:I-kappa B Kinase; D053143:Caspase 2; D020169:Caspases; C038753:leptomycin B