Differential Requirement for Caspase-1 Autoproteolysis in Pathogen-induced Cell Death and Cytokine Processing

Overview

Journal Cell Host Microbe

Publisher Cell Press

Specialties Infectious Diseases
Microbiology

Date 2010 Dec 15

PMID 21147462

Citations 328

Authors

Petr Broz

Jakob von Moltke

Jonathan W Jones

Russell E Vance

Denise M Monack

Affiliations

Soon will be listed here.

Abstract

Activation of the cysteine protease Caspase-1 is a key event in the innate immune response to infections. Synthesized as a proprotein, Caspase-1 undergoes autoproteolysis within multiprotein complexes called inflammasomes. Activated Caspase-1 is required for proteolytic processing and for release of the cytokines interleukin-1β and interleukin-18, and it can also cause rapid macrophage cell death. We show that macrophage cell death and cytokine maturation in response to infection with diverse bacterial pathogens can be separated genetically and that two distinct inflammasome complexes mediate these events. Inflammasomes containing the signaling adaptor Asc form a single large "focus" in which Caspase-1 undergoes autoproteolysis and processes IL-1β/IL-18. In contrast, Asc-independent inflammasomes activate Caspase-1 without autoproteolysis and do not form any large structures in the cytosol. Caspase-1 mutants unable to undergo autoproteolysis promoted rapid cell death, but processed IL-1β/18 inefficiently. Our results suggest the formation of spatially and functionally distinct inflammasomes complexes in response to bacterial pathogens.

Citing Articles

The vasoconstrictor adenosine 5'-tetraphosphate is a danger signal that induces IL-1β.

Bockstiegel J, Engelhardt J, Schuchardt M, Tolle M, Weindl G Mol Med. 2025; 31(1):72.

PMID: 39984847 PMC: 11844157. DOI: 10.1186/s10020-025-01116-6.

OspF blocks rapid p38-dependent priming of the NAIP-NLRC4 inflammasome.

Turcotte E, Kim K, Eislmayr K, Goers L, Mitchell P, Lesser C bioRxiv. 2025; .

PMID: 39975412 PMC: 11838452. DOI: 10.1101/2025.02.01.636075.

Activation and evasion of inflammasomes during viral and microbial infection.

Ren D, Ye X, Chen R, Jia X, He X, Tao J Cell Mol Life Sci. 2025; 82(1):56.

PMID: 39833559 PMC: 11753444. DOI: 10.1007/s00018-025-05575-2.

ATM in immunobiology: From lymphocyte development to cancer immunotherapy.

Lee J Transl Oncol. 2025; 52():102268.

PMID: 39752906 PMC: 11754496. DOI: 10.1016/j.tranon.2024.102268.

Navigating from cellular phenotypic screen to clinical candidate: selective targeting of the NLRP3 inflammasome.

Matico R, Grauwen K, Chauhan D, Yu X, Abdiaj I, Adhikary S EMBO Mol Med. 2024; 17(1):54-84.

PMID: 39653810 PMC: 11730736. DOI: 10.1038/s44321-024-00181-4.

References

Lightfield K, Persson J, Brubaker S, Witte C, von Moltke J, Dunipace E . Critical function for Naip5 in inflammasome activation by a conserved carboxy-terminal domain of flagellin. Nat Immunol. 2008; 9(10):1171-8. PMC: 2614210. DOI: 10.1038/ni.1646. 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

Stennicke H, Deveraux Q, Humke E, Reed J, Dixit V, Salvesen G . Caspase-9 can be activated without proteolytic processing. J Biol Chem. 1999; 274(13):8359-62. DOI: 10.1074/jbc.274.13.8359. View

Boatright K, Renatus M, Scott F, Sperandio S, Shin H, Pedersen I . A unified model for apical caspase activation. Mol Cell. 2003; 11(2):529-41. DOI: 10.1016/s1097-2765(03)00051-0. View

Poyet J, Srinivasula S, Tnani M, Razmara M, Fernandes-Alnemri T, Alnemri E . Identification of Ipaf, a human caspase-1-activating protein related to Apaf-1. J Biol Chem. 2001; 276(30):28309-13. DOI: 10.1074/jbc.C100250200. View

Suzuki T, Franchi L, Toma C, Ashida H, Ogawa M, Yoshikawa Y . Differential regulation of caspase-1 activation, pyroptosis, and autophagy via Ipaf and ASC in Shigella-infected macrophages. PLoS Pathog. 2007; 3(8):e111. PMC: 1941748. DOI: 10.1371/journal.ppat.0030111. View

Keller M, Ruegg A, Werner S, Beer H . Active caspase-1 is a regulator of unconventional protein secretion. Cell. 2008; 132(5):818-31. DOI: 10.1016/j.cell.2007.12.040. View

Wang S, Miura M, Jung Y, Zhu H, Li E, Yuan J . Murine caspase-11, an ICE-interacting protease, is essential for the activation of ICE. Cell. 1998; 92(4):501-9. DOI: 10.1016/s0092-8674(00)80943-5. View

Kim S, Bauernfeind F, Ablasser A, Hartmann G, Fitzgerald K, Latz E . Listeria monocytogenes is sensed by the NLRP3 and AIM2 inflammasome. Eur J Immunol. 2010; 40(6):1545-51. PMC: 3128919. DOI: 10.1002/eji.201040425. View

10.

Boyden E, Dietrich W . Nalp1b controls mouse macrophage susceptibility to anthrax lethal toxin. Nat Genet. 2006; 38(2):240-4. DOI: 10.1038/ng1724. View

11.

Elliott J, Rouge L, Wiesmann C, Scheer J . Crystal structure of procaspase-1 zymogen domain reveals insight into inflammatory caspase autoactivation. J Biol Chem. 2009; 284(10):6546-53. PMC: 2649088. DOI: 10.1074/jbc.M806121200. View

12.

Kang S, Wang S, Hara H, Peterson E, Namura S, Amin-Hanjani S . Dual role of caspase-11 in mediating activation of caspase-1 and caspase-3 under pathological conditions. J Cell Biol. 2000; 149(3):613-22. PMC: 2174843. DOI: 10.1083/jcb.149.3.613. View

13.

Brodsky I, Monack D . NLR-mediated control of inflammasome assembly in the host response against bacterial pathogens. Semin Immunol. 2009; 21(4):199-207. DOI: 10.1016/j.smim.2009.05.007. View

14.

Jones J, Kayagaki N, Broz P, Henry T, Newton K, ORourke K . Absent in melanoma 2 is required for innate immune recognition of Francisella tularensis. Proc Natl Acad Sci U S A. 2010; 107(21):9771-6. PMC: 2906881. DOI: 10.1073/pnas.1003738107. View

15.

Amer A, Franchi L, Kanneganti T, Body-Malapel M, Ozoren N, Brady G . Regulation of Legionella phagosome maturation and infection through flagellin and host Ipaf. J Biol Chem. 2006; 281(46):35217-23. DOI: 10.1074/jbc.M604933200. View

16.

Hornung V, Latz E . Critical functions of priming and lysosomal damage for NLRP3 activation. Eur J Immunol. 2010; 40(3):620-3. PMC: 3893565. DOI: 10.1002/eji.200940185. View

17.

Broz P, Newton K, Lamkanfi M, Mariathasan S, Dixit V, Monack D . Redundant roles for inflammasome receptors NLRP3 and NLRC4 in host defense against Salmonella. J Exp Med. 2010; 207(8):1745-55. PMC: 2916133. DOI: 10.1084/jem.20100257. View

18.

Ramage P, Cheneval D, Chvei M, Graff P, Hemmig R, Heng R . Expression, refolding, and autocatalytic proteolytic processing of the interleukin-1 beta-converting enzyme precursor. J Biol Chem. 1995; 270(16):9378-83. DOI: 10.1074/jbc.270.16.9378. View

19.

Martinon F, Mayor A, Tschopp J . The inflammasomes: guardians of the body. Annu Rev Immunol. 2009; 27:229-65. DOI: 10.1146/annurev.immunol.021908.132715. View

20.

Sauer J, Witte C, Zemansky J, Hanson B, Lauer P, Portnoy D . Listeria monocytogenes triggers AIM2-mediated pyroptosis upon infrequent bacteriolysis in the macrophage cytosol. Cell Host Microbe. 2010; 7(5):412-9. PMC: 2947455. DOI: 10.1016/j.chom.2010.04.004. View