A ubiquitin-independent proteasome pathway controls the CARD8 inflammasome
Hsiao, J. C.; Neugroschl, A. R.; Chui, A. J.; Taabazuing, C. Y.; Griswold, A. R.; Wang, Q.; Huang, H.-C.; Orth-He, E. L.; Ball, D. P.; Hiotis, G.; Bachovchin, D. A.
Show abstract
CARD8 is a pattern-recognition receptor that forms a caspase-1-activating inflammasome. CARD8 undergoes autoproteolysis, generating an N-terminal (NT) fragment with a disordered region and a ZU5 domain and a C-terminal (CT) fragment with UPA and CARD domains. DPP8 and DPP9 (DPP8/9) inhibitors, including Val-boroPro (VbP), accelerate the degradation of the NT fragment via a poorly characterized proteasome-mediated pathway, thereby releasing the inflammatory CT fragment from autoinhibition. Here, we show that the core 20S proteasome, which degrades disordered and misfolded proteins independent of ubiquitin, controls CARD8 activation. In unstressed cells, the 20S proteasome degrades just the NT disordered region, leaving behind the folded ZU5, UPA, and CARD domains to act as an inhibitor of inflammasome assembly. In VbP-stressed cells, the 20S proteasome degrades the entire NT fragment, perhaps due to ZU5 domain unfolding, freeing the CT fragment from autoinhibition. Overall, this work shows that CARD8 NTs susceptibility to 20S proteasome-mediated degradation controls inflammasome activation.
Matching journals
The top 4 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Immune dysregulation in SHARPIN-deficient mice is dependent on CYLD-mediated cell death 96%
- Temporal control of acute protein aggregate turnover by UBE3C and NRF1-dependent proteasomal pathways 95%
- RIPK1 activates distinct gasdermins in macrophages and neutrophils upon pathogen blockade of innate immune signalling 95%
Similar papers in this journal
Similar papers in this journal
Similar papers in this journal
- An Abundance of Free Proteasomal Regulatory (19S) Particles Regulate Neuronal Synapses Independent of the Proteasome 95%
- Identification and receptor mechanism of TIR-catalyzed small molecules in plant immunity 94%
- Architecture of the UBR4 complex, a giant E4 ligase central to eukaryotic protein quality control 93%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.