DIPTAR: A synthetic biology platform for functional interrogation of protein degradation
Exconder, P. M.; Yoo, W.; Kulkarni, M.; Mahale, A. B.; Myers, B. E.; Patio, R. C.; Bourne, C. M.; Discher, B. M.; Taabazuing, C. Y.
Show abstract
Protein degradation regulates cellular homeostasis, yet many degradation events are difficult to study because they lack a readily selectable phenotype. Here, we develop Degradation-Induced Pyroptosis TArgeting Receptors (DIPTAR), a modular synthetic biology platform that couples protein degradation to CARD8-mediated pyroptosis. Using HIF-1 as a model substrate, we show that DIPTAR faithfully reports oxygen-dependent VHL-mediated degradation and enables pooled CRISPR screening to identify established and previously unrecognized regulators of HIF-1 stability. DIPTAR is functional across multiple cell types and can be programmed with diverse proteins, including BRD4, I{kappa}B, and p53, to convert distinct degradation stimuli into a common pyroptotic output. DIPTAR also detects pathogen-mediated perturbations of host degradation pathways, including both inhibition and induction of degradation-dependent signaling. By converting protein degradation into a robust selectable phenotype, DIPTAR provides a scalable platform for functional genetic discovery, interrogation of degradation pathways, degrader characterization, and investigation of host-pathogen interactions.
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