An Inhibitor of PIDDosome Formation

• Published in: Molecular cell Vol. 58; no. 5; pp. 767 - 779
• Main Authors: Thompson, Ruth, Shah, Richa B., Liu, Peter H., Gupta, Yogesh K., Ando, Kiyohiro, Aggarwal, Aneel K., Sidi, Samuel
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.06.2015
• Subjects: Animals; Caspase 2 - metabolism; Cysteine Endopeptidases - metabolism; Death Domain Receptor Signaling Adaptor Proteins - metabolism; DNA Damage; HCT116 Cells; HeLa Cells; Humans; Kinetochores - enzymology; Mad2 Proteins - metabolism; Mice; Phosphorylation; Protein Processing, Post-Translational; Protein-Serine-Threonine Kinases - physiology; Signal Transduction
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2015.03.034

The PIDDosome—PIDD-RAIDD-caspase-2 complex—is a proapoptotic caspase-activation platform of elusive significance. DNA damage can initiate complex assembly via ATM phosphorylation of the PIDD death domain (DD), which enables RAIDD recruitment to PIDD. In contrast, the mechanisms limiting PIDDosome formation have remained unclear. We identify the mitotic checkpoint factor BubR1 as a direct PIDDosome inhibitor, acting in a noncanonical role independent of Mad2. Following its phosphorylation by ATM at DNA breaks, “primed” PIDD relocates to kinetochores via a direct interaction with BubR1. BubR1 binds the PIDD DD, competes with RAIDD recruitment, and negates PIDDosome-mediated apoptosis after ionizing radiation. The PIDDosome thus sequentially integrates DNA damage and mitotic checkpoint signals to decide cell fate in response to genotoxic stress. We further show that by sequestering PIDD at the kinetochore, BubR1 acts to delay PIDDosome formation until the next cycle, defining a new mechanism by which cells evade apoptosis during mitosis. [Display omitted] •BubR1, but not Mad2, suppresses PIDDosome-mediated apoptosis after DNA damage•BubR1 recruits ATM-phosphorylated PIDD to kinetochores during mitosis•BubR1 outcompetes RAIDD at the PIDD death domain•DNA-damage-induced PIDDosome assembly requires mitotic exit The PIDDosome is a caspase-activation platform of elusive regulators and substrates. Here, Thompson et al. identify the mitotic checkpoint effector BubR1 as a PIDDosome inhibitor, acting at the kinetochore to prevent complex assembly during mitosis. Mechanistically, BubR1 competes with docking of the platform’s caspase adaptor, RAIDD, onto the PIDD scaffold.