Recognition and Maturation of IL-18 by Caspase-4 Noncanonical Inflammasome

Overview

Journal Nature

Specialty Science

Date 2023 Nov 22

PMID 37993714

Authors

Xuyan Shi

Qichao Sun

Yanjie Hou

Huan Zeng

Yong Cao

Mengqiu Dong

Jingjin Ding

Feng Shao

Affiliations

Soon will be listed here.

Abstract

The canonical (caspase-1) and noncanonical (comprising caspases 4, 5 and 11; hereafter, caspase-4/5/11) inflammasomes both cleave gasdermin D (GSDMD) to induce pyroptosis. Whereas caspase-1 processes IL-1β and IL-18 for maturation, no cytokine target has been firmly established for lipopolysaccharide-activated caspase-4/5/11. Here we show that activated human caspase-4, but not mouse caspase-11, directly and efficiently processes IL-18 in vitro and during bacterial infections. Caspase-4 cleaves the same tetrapeptide site in pro-IL-18 as caspase-1. The crystal structure of the caspase-4-pro-IL-18 complex reveals a two-site (binary) substrate-recognition mechanism; the catalytic pocket engages the tetrapeptide, and a unique exosite that critically recognizes GSDMD similarly binds to a specific structure formed jointly by the propeptide and post-cleavage-site sequences in pro-IL-18. This binary recognition is also used by caspase-5 as well as caspase-1 to process pro-IL-18. In caspase-11, a structural deviation around the exosite underlies its inability to target pro-IL-18, which is restored by rationally designed mutations. The structure of pro-IL-18 features autoinhibitory interactions between the propeptide and the post-cleavage-site region, preventing recognition by the IL-18Rα receptor. Cleavage by caspase-1, -4 or -5 induces substantial conformational changes of IL-18 to generate two critical receptor-binding sites. Our study establishes IL-18 as a target of lipopolysaccharide-activated caspase-4/5. The finding is paradigm shifting in the understanding of noncanonical-inflammasome-mediated defences and also the function of IL-18 in immunity and disease.

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References

Kayagaki N, Stowe I, Lee B, ORourke K, Anderson K, Warming S . Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature. 2015; 526(7575):666-71. DOI: 10.1038/nature15541. View

Shi J, Zhao Y, Wang K, Shi X, Wang Y, Huang H . Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature. 2015; 526(7575):660-5. DOI: 10.1038/nature15514. View

Cerretti D, Kozlosky C, Mosley B, Nelson N, van Ness K, Greenstreet T . Molecular cloning of the interleukin-1 beta converting enzyme. Science. 1992; 256(5053):97-100. DOI: 10.1126/science.1373520. View

Thornberry N, Bull H, Calaycay J, Chapman K, Howard A, Kostura M . A novel heterodimeric cysteine protease is required for interleukin-1 beta processing in monocytes. Nature. 1992; 356(6372):768-74. DOI: 10.1038/356768a0. View

Ghayur T, Banerjee S, Hugunin M, Butler D, Herzog L, Carter A . Caspase-1 processes IFN-gamma-inducing factor and regulates LPS-induced IFN-gamma production. Nature. 1997; 386(6625):619-23. DOI: 10.1038/386619a0. View

Gu Y, Kuida K, Tsutsui H, Ku G, Hsiao K, Fleming M . Activation of interferon-gamma inducing factor mediated by interleukin-1beta converting enzyme. Science. 1997; 275(5297):206-9. DOI: 10.1126/science.275.5297.206. View

Shi J, Zhao Y, Wang Y, Gao W, Ding J, Li P . Inflammatory caspases are innate immune receptors for intracellular LPS. Nature. 2014; 514(7521):187-92. DOI: 10.1038/nature13683. View

Kayagaki N, Warming S, Lamkanfi M, Vande Walle L, Louie S, Dong J . Non-canonical inflammasome activation targets caspase-11. Nature. 2011; 479(7371):117-21. DOI: 10.1038/nature10558. View

Li Z, Liu W, Fu J, Cheng S, Xu Y, Wang Z . Shigella evades pyroptosis by arginine ADP-riboxanation of caspase-11. Nature. 2021; 599(7884):290-295. DOI: 10.1038/s41586-021-04020-1. View

10.

Wang K, Sun Q, Zhong X, Zeng M, Zeng H, Shi X . Structural Mechanism for GSDMD Targeting by Autoprocessed Caspases in Pyroptosis. Cell. 2020; 180(5):941-955.e20. DOI: 10.1016/j.cell.2020.02.002. View

11.

Broz P, Dixit V . Inflammasomes: mechanism of assembly, regulation and signalling. Nat Rev Immunol. 2016; 16(7):407-20. DOI: 10.1038/nri.2016.58. View

12.

Ding J, Wang K, Liu W, She Y, Sun Q, Shi J . Pore-forming activity and structural autoinhibition of the gasdermin family. Nature. 2016; 535(7610):111-6. DOI: 10.1038/nature18590. View

13.

Liu X, Zhang Z, Ruan J, Pan Y, Magupalli V, Wu H . Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature. 2016; 535(7610):153-8. PMC: 5539988. DOI: 10.1038/nature18629. View

14.

Xia S, Zhang Z, Magupalli V, Pablo J, Dong Y, Vora S . Gasdermin D pore structure reveals preferential release of mature interleukin-1. Nature. 2021; 593(7860):607-611. PMC: 8588876. DOI: 10.1038/s41586-021-03478-3. View

15.

Broz P, Pelegrin P, Shao F . The gasdermins, a protein family executing cell death and inflammation. Nat Rev Immunol. 2019; 20(3):143-157. DOI: 10.1038/s41577-019-0228-2. View

16.

Jorgensen I, Zhang Y, Krantz B, Miao E . Pyroptosis triggers pore-induced intracellular traps (PITs) that capture bacteria and lead to their clearance by efferocytosis. J Exp Med. 2016; 213(10):2113-28. PMC: 5030797. DOI: 10.1084/jem.20151613. View

17.

Man S, Karki R, Kanneganti T . Molecular mechanisms and functions of pyroptosis, inflammatory caspases and inflammasomes in infectious diseases. Immunol Rev. 2017; 277(1):61-75. PMC: 5416822. DOI: 10.1111/imr.12534. View

18.

Evavold C, Ruan J, Tan Y, Xia S, Wu H, Kagan J . The Pore-Forming Protein Gasdermin D Regulates Interleukin-1 Secretion from Living Macrophages. Immunity. 2017; 48(1):35-44.e6. PMC: 5773350. DOI: 10.1016/j.immuni.2017.11.013. View

19.

Heilig R, Dick M, Sborgi L, Meunier E, Hiller S, Broz P . The Gasdermin-D pore acts as a conduit for IL-1β secretion in mice. Eur J Immunol. 2017; 48(4):584-592. DOI: 10.1002/eji.201747404. View

20.

Kim M, Chae J, Park Y, De Nardo D, Stirzaker R, Ko H . Aberrant actin depolymerization triggers the pyrin inflammasome and autoinflammatory disease that is dependent on IL-18, not IL-1β. J Exp Med. 2015; 212(6):927-38. PMC: 4451132. DOI: 10.1084/jem.20142384. View