Chemical Modulation of Gasdermin D Activity: Therapeutic Implications and Consequences

Overview

Journal Semin Immunol

Specialty Allergy & Immunology

Date 2023 Oct 8

PMID 37806032

Authors

Bowen Zhou

Derek W Abbott

Affiliations

Soon will be listed here.

Abstract

The gasdermin family of proteins are central effectors of the inflammatory, lytic cell death modality known as pyroptosis. Characterized in 2015, the most well-studied member gasdermin D can be proteolyzed, typically by caspases, to generate an active pore-forming N-terminal domain. At least well-studied three pharmacological inhibitors (necrosulfonamide, disulfiram, dimethyl fumarate) since 2018 have been shown to affect gasdermin D activity either through modulation of processing or interference with pore formation. A multitude of murine in vivo studies have since followed. Here, we discuss the current state of research surrounding these three inhibitors, caveats to their use, and a set of guiding principles that researchers should consider when pursuing further studies of gasdermin D inhibition.

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References

Sollberger G, Choidas A, Burn G, Habenberger P, Di Lucrezia R, Kordes S . Gasdermin D plays a vital role in the generation of neutrophil extracellular traps. Sci Immunol. 2018; 3(26). DOI: 10.1126/sciimmunol.aar6689. View

Borges J, Saetra R, Volchuk A, Bugge M, Devant P, Sporsheim B . Glycine inhibits NINJ1 membrane clustering to suppress plasma membrane rupture in cell death. Elife. 2022; 11. PMC: 9754625. DOI: 10.7554/eLife.78609. View

Gutierrez K, Davis M, Daniels B, Olsen T, Ralli-Jain P, Tait S . MLKL Activation Triggers NLRP3-Mediated Processing and Release of IL-1β Independently of Gasdermin-D. J Immunol. 2017; 198(5):2156-2164. PMC: 5321867. DOI: 10.4049/jimmunol.1601757. View

Schneider K, Gross C, Dreier R, Saller B, Mishra R, Gorka O . The Inflammasome Drives GSDMD-Independent Secondary Pyroptosis and IL-1 Release in the Absence of Caspase-1 Protease Activity. Cell Rep. 2017; 21(13):3846-3859. PMC: 5750195. DOI: 10.1016/j.celrep.2017.12.018. View

Wu Y, Ou W, Zhong M, Lin S, Zhu Y . Gasdermin D Inhibitor Necrosulfonamide Alleviates Lipopolysaccharide/D-galactosamine-induced Acute Liver Failure in Mice. J Clin Transl Hepatol. 2022; 10(6):1148-1154. PMC: 9634782. DOI: 10.14218/JCTH.2021.00560. View

He W, Wan H, Hu L, Chen P, Wang X, Huang Z . Gasdermin D is an executor of pyroptosis and required for interleukin-1β secretion. Cell Res. 2015; 25(12):1285-98. PMC: 4670995. DOI: 10.1038/cr.2015.139. View

Weir A, Vince J . No longer married to inflammasome signaling: the diverse interacting pathways leading to pyroptotic cell death. Biochem J. 2022; 479(10):1083-1102. PMC: 9162454. DOI: 10.1042/BCJ20210711. View

Liu Z, Wang C, Yang J, Chen Y, Zhou B, Abbott D . Caspase-1 Engages Full-Length Gasdermin D through Two Distinct Interfaces That Mediate Caspase Recruitment and Substrate Cleavage. Immunity. 2020; 53(1):106-114.e5. PMC: 7382298. DOI: 10.1016/j.immuni.2020.06.007. View

Taabazuing C, Okondo M, Bachovchin D . Pyroptosis and Apoptosis Pathways Engage in Bidirectional Crosstalk in Monocytes and Macrophages. Cell Chem Biol. 2017; 24(4):507-514.e4. PMC: 5467448. DOI: 10.1016/j.chembiol.2017.03.009. View

10.

Chen K, Demarco B, Heilig R, Shkarina K, Boettcher A, Farady C . Extrinsic and intrinsic apoptosis activate pannexin-1 to drive NLRP3 inflammasome assembly. EMBO J. 2019; 38(10). PMC: 6517827. DOI: 10.15252/embj.2019101638. View

11.

Conos S, Chen K, De Nardo D, Hara H, Whitehead L, Nunez G . Active MLKL triggers the NLRP3 inflammasome in a cell-intrinsic manner. Proc Natl Acad Sci U S A. 2017; 114(6):E961-E969. PMC: 5307433. DOI: 10.1073/pnas.1613305114. View

12.

Zhou B, Abbott D . Gasdermin E permits interleukin-1 beta release in distinct sublytic and pyroptotic phases. Cell Rep. 2021; 35(2):108998. PMC: 8106763. DOI: 10.1016/j.celrep.2021.108998. View

13.

Hanson J, Gille A, Zwykiel S, Lukasova M, Clausen B, Ahmed K . Nicotinic acid- and monomethyl fumarate-induced flushing involves GPR109A expressed by keratinocytes and COX-2-dependent prostanoid formation in mice. J Clin Invest. 2010; 120(8):2910-9. PMC: 2912194. DOI: 10.1172/JCI42273. View

14.

Chen H, Assmann J, Krenz A, Rahman M, Grimm M, Karsten C . Hydroxycarboxylic acid receptor 2 mediates dimethyl fumarate's protective effect in EAE. J Clin Invest. 2014; 124(5):2188-92. PMC: 4001545. DOI: 10.1172/JCI72151. View

15.

Cookson B, Brennan M . Pro-inflammatory programmed cell death. Trends Microbiol. 2001; 9(3):113-4. DOI: 10.1016/s0966-842x(00)01936-3. View

16.

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

17.

Heilig R, Dilucca M, Boucher D, Chen K, Hancz D, Demarco B . Caspase-1 cleaves Bid to release mitochondrial SMAC and drive secondary necrosis in the absence of GSDMD. Life Sci Alliance. 2020; 3(6). PMC: 7190276. DOI: 10.26508/lsa.202000735. View

18.

Gold R, Kappos L, Arnold D, Bar-Or A, Giovannoni G, Selmaj K . Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012; 367(12):1098-107. DOI: 10.1056/NEJMoa1114287. View

19.

Gullett J, Tweedell R, Kanneganti T . It's All in the PAN: Crosstalk, Plasticity, Redundancies, Switches, and Interconnectedness Encompassed by PANoptosis Underlying the Totality of Cell Death-Associated Biological Effects. Cells. 2022; 11(9). PMC: 9105755. DOI: 10.3390/cells11091495. View

20.

Humphries F, Shmuel-Galia L, Ketelut-Carneiro N, Li S, Wang B, Nemmara V . Succination inactivates gasdermin D and blocks pyroptosis. Science. 2020; 369(6511):1633-1637. PMC: 8744141. DOI: 10.1126/science.abb9818. View