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Structural basis for distinct inflammasome complex assembly by human NLRP1 and CARD8.

<div class='caption-title'>Human NLRP1 inflammasome complexes.</div>
<div class='caption-title'>Cryo-EM structures of NLRP1-CARD and CARD8-CARD filaments.</div>
<div class='caption-title'>Model of two-layer organization of NLRP1 and CARD8 FIINDUPA-CARD filaments.</div>
Gong Q, Robinson K, Xu C, Huynh PT, Chong KHC, Tan EYJ, Zhang J, Boo ZZ, Teo DET, Lay K, Zhang Y, Lim JSY, Goh WI, Wright G, Zhong FL, Reversade B, Wu B
OpenAccess logo Nat Commun 12 188 (2021)
Related entries: 6k7v, 6k8j, 6k99

Cited: 34 times
EuropePMC logo PMID: 33420028

Abstract

Nod-like receptor (NLR) proteins activate pyroptotic cell death and IL-1 driven inflammation by assembling and activating the inflammasome complex. Closely related sensor proteins NLRP1 and CARD8 undergo unique auto-proteolysis-dependent activation and are implicated in auto-inflammatory diseases; however, their mechanisms of activation are not understood. Here we report the structural basis of how the activating domains (FIINDUPA-CARD) of NLRP1 and CARD8 self-oligomerize to assemble distinct inflammasome complexes. Recombinant FIINDUPA-CARD of NLRP1 forms a two-layered filament, with an inner core of oligomerized CARD surrounded by an outer ring of FIINDUPA. Biochemically, self-assembled NLRP1-CARD filaments are sufficient to drive ASC speck formation in cultured human cells-a process that is greatly enhanced by NLRP1-FIINDUPA which forms oligomers in vitro. The cryo-EM structures of NLRP1-CARD and CARD8-CARD filaments, solved here at 3.7 Å, uncover unique structural features that enable NLRP1 and CARD8 to discriminate between ASC and pro-caspase-1. In summary, our findings provide structural insight into the mechanisms of activation for human NLRP1 and CARD8 and reveal how highly specific signaling can be achieved by heterotypic CARD interactions within the inflammasome complexes.

Articles - 6k9f mentioned but not cited (1)

  1. Structural basis for distinct inflammasome complex assembly by human NLRP1 and CARD8. Gong Q, Robinson K, Xu C, Huynh PT, Chong KHC, Tan EYJ, Zhang J, Boo ZZ, Teo DET, Lay K, Zhang Y, Lim JSY, Goh WI, Wright G, Zhong FL, Reversade B, Wu B. Nat Commun 12 188 (2021)


Reviews citing this publication (17)

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  2. The evolution of regulated cell death pathways in animals and their evasion by pathogens. Tummers B, Green DR. Physiol Rev 102 411-454 (2022)
  3. The role of inflammasomes in vascular cognitive impairment. Poh L, Sim WL, Jo DG, Dinh QN, Drummond GR, Sobey CG, Chen CL, Lai MKP, Fann DY, Arumugam TV. Mol Neurodegener 17 4 (2022)
  4. Structures and functions of the inflammasome engine. Wang L, Sharif H, Vora SM, Zheng Y, Wu H. J Allergy Clin Immunol 147 2021-2029 (2021)
  5. Mechanistic Insights into Gasdermin Pore Formation and Regulation in Pyroptosis. Wang C, Ruan J. J Mol Biol 434 167297 (2022)
  6. Human NLRP1: From the shadows to center stage. Bauernfried S, Hornung V. J Exp Med 219 e20211405 (2022)
  7. Chemical Modulation of Gasdermin-Mediated Pyroptosis and Therapeutic Potential. Ryder CB, Kondolf HC, O'Keefe ME, Zhou B, Abbott DW. J Mol Biol 434 167183 (2022)
  8. Activation and regulation mechanisms of NOD-like receptors based on structural biology. Ohto U. Front Immunol 13 953530 (2022)
  9. No longer married to inflammasome signaling: the diverse interacting pathways leading to pyroptotic cell death. Weir A, Vince JE. Biochem J 479 1083-1102 (2022)
  10. New insights into the role of dipeptidyl peptidase 8 and dipeptidyl peptidase 9 and their inhibitors. Cui C, Tian X, Wei L, Wang Y, Wang K, Fu R. Front Pharmacol 13 1002871 (2022)
  11. Structural mechanisms of inflammasome regulation revealed by cryo-EM studies. Cao J, Nash G, Zhang L. Curr Opin Struct Biol 75 102390 (2022)
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  13. The roles of inflammasomes in cancer. Deng Z, Lu L, Li B, Shi X, Jin H, Hu W. Front Immunol 14 1195572 (2023)
  14. The role of inflammasomes in human diseases and their potential as therapeutic targets. Yao J, Sterling K, Wang Z, Zhang Y, Song W. Signal Transduct Target Ther 9 10 (2024)
  15. Mechanistic insights from inflammasome structures. Fu J, Schroder K, Wu H. Nat Rev Immunol (2024)
  16. NLRP1- A CINDERELLA STORY: a perspective of recent advances in NLRP1 and the questions they raise. Barry K, Murphy C, Mansell A. Commun Biol 6 1274 (2023)
  17. Pyroptosis: the dawn of a new era in endometrial cancer treatment. Peng T, Zhang C, Chen WJ, Zhao XF, Wu WB, Yang WJ, Liang RJ. Front Oncol 13 1277639 (2023)

Articles citing this publication (16)



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