N-GSDMD trafficking to neutrophil organelles facilitates IL-1β release independently of plasma membrane pores and pyroptosis

Mausita Karmakar, Martin Minns, Elyse N. Greenberg, Jose Diaz-Aponte, Kersi Pestonjamasp, Jennifer L. Johnson, Joseph K. Rathkey, Derek W. Abbott, Kun Wang, Feng Shao, Sergio D. Catz, George R. Dubyak () and Eric Pearlman ()
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Mausita Karmakar: Case Western Reserve University
Martin Minns: University of California
Elyse N. Greenberg: University of California
Jose Diaz-Aponte: Case Western Reserve University
Kersi Pestonjamasp: The Scripps Research Institute
Jennifer L. Johnson: The Scripps Research Institute
Joseph K. Rathkey: Case Western Reserve University
Derek W. Abbott: Case Western Reserve University
Kun Wang: National Institute of Biological Sciences
Feng Shao: National Institute of Biological Sciences
Sergio D. Catz: The Scripps Research Institute
George R. Dubyak: Case Western Reserve University
Eric Pearlman: University of California

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract Gasdermin-D (GSDMD) in inflammasome-activated macrophages is cleaved by caspase-1 to generate N-GSDMD fragments. N-GSDMD then oligomerizes in the plasma membrane (PM) to form pores that increase membrane permeability, leading to pyroptosis and IL-1β release. In contrast, we report that although N-GSDMD is required for IL-1β secretion in NLRP3-activated human and murine neutrophils, N-GSDMD does not localize to the PM or increase PM permeability or pyroptosis. Instead, biochemical and microscopy studies reveal that N-GSDMD in neutrophils predominantly associates with azurophilic granules and LC3+ autophagosomes. N-GSDMD trafficking to azurophilic granules causes leakage of neutrophil elastase into the cytosol, resulting in secondary cleavage of GSDMD to an alternatively cleaved N-GSDMD product. Genetic analyses using ATG7-deficient cells indicate that neutrophils secrete IL-1β via an autophagy-dependent mechanism. These findings reveal fundamental differences in GSDMD trafficking between neutrophils and macrophages that underlie neutrophil-specific functions during inflammasome activation.

Date: 2020
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DOI: 10.1038/s41467-020-16043-9

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