Recent studies have identified Cys in gasdermin D (GSDMD) as a highly targeted regulatory module controlling pyroptosis. Using chemical biology and genetic models, Du, Healy et al. recently identified GSDMD palmitoylation as a key regulatory step in GSDMD activation.
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Emerging roles of palmitoylation in pyroptosis.
Trends Cell Biol
November 2024
Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 201210, China; State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 200032, China; Shanghai Key Laboratory of Aging Studies, Shanghai, 201210, China. Electronic address:
Pyroptosis is a lytic, proinflammatory type of programmed cell death crucial for the immune response to pathogen infections and internal danger signals. Gasdermin D (GSDMD) acts as the pore-forming protein in pyroptosis following inflammasome activation. While recent research has improved our understanding of pyroptosis activation and execution, many aspects regarding the molecular mechanisms controlling inflammasome and GSDMD activation remain to be elucidated.
View Article and Find Full Text PDFMultifunctional Copper-Phenolic Nanopills Achieve Comprehensive Polyamines Depletion to Provoke Enhanced Pyroptosis and Cuproptosis for Cancer Immunotherapy.
Adv Mater
November 2024
Institute of Frontier Chemistry, School of Chemistry and Chemical Engineering, Shandong University, Qingdao, 266237, P. R. China.
The overexpression of polyamines in tumor cells contributes to the establishment of immunosuppressive microenvironment and facilitates tumor growth. Here, it have ingeniously designed multifunctional copper-piceatannol/HA nanopills (Cu-Pic/HA NPs) that effectively cause total intracellular polyamines depletion by inhibiting polyamines synthesis, depleting intracellular polyamines, and impairing polyamines uptake, resulting in enhanced pyroptosis and cuproptosis, thus activating a powerful immune response to achieve anti-tumor therapy. Mitochondrial dysfunction resulting from overall intracellular polyamines depletion not only leads to the surge of copper ions in mitochondria, thereby causing the aggregation of toxic proteins to induce cuproptosis, but also triggers the accumulation of reactive oxygen species (ROS) within mitochondria, which further upregulates the expression of zDHHC5 and zDHHC9 to promote the palmitoylation of gasdermin D (GSDMD) and GSDMD-N, ultimately inducing enhanced pyroptosis.
View Article and Find Full Text PDFGasdermin D cysteine residues synergistically control its palmitoylation-mediated membrane targeting and assembly.
EMBO J
October 2024
Department of Biology/Chemistry and Center for Cellular Nanoanalytics (CellNanOs), University of Osnabrück, Osnabrück, Germany.
Gasdermin D (GSDMD) executes the cell death program of pyroptosis by assembling into oligomers that permeabilize the plasma membrane. Here, by single-molecule imaging, we elucidate the yet unclear mechanism of Gasdermin D pore assembly and the role of cysteine residues in GSDMD oligomerization. We show that GSDMD preassembles at the membrane into dimeric and trimeric building blocks that can either be inserted into the membrane, or further assemble into higher-order oligomers prior to insertion into the membrane.
View Article and Find Full Text PDFFDA-approved disulfiram inhibits the NLRP3 inflammasome by regulating NLRP3 palmitoylation.
Cell Rep
August 2024
Department of Pathology and Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Electronic address:
The NLRP3 inflammasome is dysregulated in autoinflammatory disorders caused by inherited mutations and contributes to the pathogenesis of several chronic inflammatory diseases. In this study, we discovered that disulfiram, a safe US Food and Drug Administration (FDA)-approved drug, specifically inhibits the NLRP3 inflammasome but not the NLRC4 or AIM2 inflammasomes. Disulfiram suppresses caspase-1 activation, ASC speck formation, and pyroptosis induced by several stimuli that activate NLRP3.
View Article and Find Full Text PDFPalmitoylation at a conserved cysteine residue facilitates gasdermin D-mediated pyroptosis and cytokine release.
Proc Natl Acad Sci U S A
July 2024
Department of Pathology, Case Western Reserve University, Cleveland, OH 44106.
Gasdermin D (GSDMD)-mediated pyroptotic cell death drives inflammatory cytokine release and downstream immune responses upon inflammasome activation, which play important roles in host defense and inflammatory disorders. Upon activation by proteases, the GSDMD N-terminal domain (NTD) undergoes oligomerization and membrane translocation in the presence of lipids to assemble pores. Despite intensive studies, the molecular events underlying the transition of GSDMD from an autoinhibited soluble form to an oligomeric pore form inserted into the membrane remain incompletely understood.
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