2. Academic Validation
  3. Activation of the CARD8 Inflammasome Requires a Disordered Region

Activation of the CARD8 Inflammasome Requires a Disordered Region

  • Cell Rep. 2020 Oct 13;33(2):108264. doi: 10.1016/j.celrep.2020.108264.
Ashley J Chui 1,  Andrew R Griswold 2,  Cornelius Y Taabazuing 3,  Elizabeth L Orth 1,  Kuo Gai 3,  Sahana D Rao 1,  Daniel P Ball 3,  Jeffrey C Hsiao 4,  Daniel A Bachovchin 5
Affiliations

Affiliations

  • 1 Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 2 Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program, New York, NY 10065, USA.
  • 3 Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 4 Pharmacology Program of the Weill Cornell Graduate School of Medical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 5 Tri-Institutional PhD Program in Chemical Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Chemical Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Pharmacology Program of the Weill Cornell Graduate School of Medical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: [email protected].
PMID: 33053349 DOI: 10.1016/j.celrep.2020.108264
Abstract

Several cytosolic pattern-recognition receptors (PRRs) form multiprotein complexes called canonical inflammasomes in response to intracellular danger signals. Canonical inflammasomes recruit and activate Caspase-1 (CASP1), which in turn cleaves and activates inflammatory cytokines and gasdermin D (GSDMD), inducing pyroptotic cell death. Inhibitors of the dipeptidyl peptidases DPP8 and DPP9 (DPP8/9) activate both the human NLRP1 and CARD8 inflammasomes. NLRP1 and CARD8 have different N-terminal regions but have similar C-terminal regions that undergo autoproteolysis to generate two non-covalently associated fragments. Here, we show that DPP8/9 inhibition activates a proteasomal degradation pathway that targets disordered and misfolded proteins for destruction. CARD8's N terminus contains a disordered region of ∼160 Amino acids that is recognized and destroyed by this degradation pathway, thereby freeing its C-terminal fragment to activate CASP1 and induce Pyroptosis. Thus, CARD8 serves as an alarm to signal the activation of a degradation pathway for disordered and misfolded proteins.

Keywords

CARD8; DPP8/9; Val-boroPro; inflammasomes; proteasome; protein disorder.

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