biostudies-literatureYeh TCNCI NIH HHSNIGMS NIH HHS14284-9https://www.ebi.ac.uk/biostudies/studies/S-EPMC3761634biostudies-literatureUnknown110(35)Drosophila inhibitor of apoptosis (IAP) 1 (DIAP1) is an E3 ubiquitin ligase that regulates apoptosis in flies, in large part through direct inhibition and/or ubiquitinylation of caspases. IAP antagonists, such as Reaper, Hid, and Grim, are thought to induce cell death by displacing active caspases from baculovirus IAP repeat domains in DIAP1, but can themselves become targets of DIAP1-mediated ubiquitinylation. Herein, we demonstrate that Grim self-associates in cells and is ubiquitinylated by DIAP1 at Lys136 in an UbcD1-dependent manner, resulting in its rapid turnover. K48-linked ubiquitin chains are added almost exclusively to BIR2-bound Grim as a result of its structural proximity to DIAP1's RING domain. However, active caspases can simultaneously cleave Grim at Asp132, removing the lyProceedings of the National Academy of Sciences of the United States of AmericaCaspase-dependent regulation of the ubiquitin-proteasome system through direct substrate targeting.PMC3761634P30 CA016672GM096101R01 GM096101CA129521R01 CA129521Bratton SBYeh TCfalseCaspase-dependent regulation of the ubiquitin-proteasome system through direct substrate targeting.Drosophila inhibitor of apoptosis (IAP) 1 (DIAP1) is an E3 ubiquitin ligase that regulates apoptosis in flies, in large part through direct inhibition and/or ubiquitinylation of caspases. IAP antagonists, such as Reaper, Hid, and Grim, are thought to induce cell death by displacing active caspases from baculovirus IAP repeat domains in DIAP1, but can themselves become targets of DIAP1-mediated ubiquitinylation. Herein, we demonstrate that Grim self-associates in cells and is ubiquitinylated by DIAP1 at Lys136 in an UbcD1-dependent manner, resulting in its rapid turnover. K48-linked ubiquitin chains are added almost exclusively to BIR2-bound Grim as a result of its structural proximity to DIAP1's RING domain. However, active caspases can simultaneously cleave Grim at Asp132, removing the ly2013-01-01T00:00:00Z2013 Aug2025-04-07T11:14:15.834Z2019-03-27T01:15:28ZS-EPMC37616342394036710.1073/pnas.1306179110